Drug delivery medical device

ABSTRACT

Provided is a coated implantable medical device, comprising: a substrate; and a coating disposed on said substrate, wherein said coating comprises at least one polymer and at least one pharmaceutical agent in a therapeutically desirable morphology and/or at least one active biological agent and optionally, one or more pharmaceutical carrying agents; wherein substantially all of pharmaceutical agent and/or active biological agent remains within said coating and on said substrate until the implantable device is deployed at an intervention site inside the body of a subject and wherein upon deployment of said medical device in the body of said subject a portion of said pharmaceutical agent and/or active biological agent is delivered at said intervention site along with at least a portion of said polymer and/or a at least a portion of said pharmaceutical carrying agents.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.61/081,691, filed Jul. 17, 2008; and U.S. Provisional Application No.61/212,964, filed Apr. 17, 2009, and U.S. Provisional Application No.61/162,558, filed Mar. 23, 2009, which applications are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

There is a need for medical device technology that can rapidly,efficiently, reproducibly and safely transfer a Drug DeliveryFormulation from the surface of a percutaneous medical device (acoating) onto/into a specific site in the body.

SUMMARY OF THE INVENTION

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent that is crystalline, and wherein the device isadapted to free at least a portion of the coating from the substrateupon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent that is crystalline, and wherein the device isadapted to dissociate at least a portion of the coating from thesubstrate upon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent that is crystalline, and wherein the device isadapted to transfer at least a portion of the coating from the substrateto an intervention site upon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating is atleast partially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent that is crystalline, andwherein the device is adapted to free at least a portion of the coatingfrom the substrate upon stimulation of the coating.

Provided herein is a medical device comprising: a substrate and acoating on at least a portion of said substrate, wherein said coating isat least partially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent that is crystalline, andwherein the device is adapted to dissociate at least a portion of thecoating from the substrate upon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating is atleast partially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent that is crystalline, andwherein the device is adapted to transfer at least a portion of thecoating from the substrate to an intervention site upon stimulation ofthe coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, and wherein the device is adapted to free greater than35% of the coating from the substrate upon a single stimulation of thecoating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, and wherein the device is adapted to dissociate greaterthan 35% of the coating from the substrate upon a single stimulation ofthe coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, and wherein the device is adapted to transfer greaterthan 35% of the coating from the substrate to an intervention site upona single stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, wherein the coating is patterned, and wherein at leasta portion of the coating is adapted to free from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, wherein the coating is patterned, and wherein at leasta portion of the coating is adapted to dissociate from the substrateupon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, wherein the coating is patterned, and wherein at leasta portion of the coating is adapted to transfer from the substrate to anintervention site upon stimulation of the coating.

In some embodiments, the therapeutically desirable morphology comprisesa crystalline form of the pharmaceutical agent that is not amicrocapsule.

In some embodiments, the single stimulation lasts at most 20 seconds. Insome embodiments, the device is adapted to free substantially all of thecoating upon the single stimulation of the coating. In some embodiments,the single stimulation lasts at most 20 seconds. In some embodiments,substantially all of the coating frees from the substrateinstantaneously upon stimulation of the coating.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein at least a portion of the coatingis adapted to transfer from the substrate to an intervention site. Insome embodiments, the portion of the coating is adapted to transfer fromthe substrate to the intervention site upon stimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein at least a portion of the activeagent is adapted to transfer from the substrate to an intervention site.In some embodiments, the portion of the active agent is adapted totransfer from the substrate to the intervention site upon stimulation ofthe coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein the device is adapted to transferat least a portion of the coating from the substrate to an interventionsite. In some embodiments, the device is adapted to transfer the portionof the coating (coating portion) from the substrate to the interventionsite upon stimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein the device is adapted to transferat least a portion of the active agent from the substrate to anintervention site. In some embodiments, the device is adapted totransfer the portion of the active agent from the substrate to theintervention site upon stimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, wherein the device is adapted to free atleast a portion of the coating from the substrate at an interventionsite. In some embodiments, the device is adapted to free the portion ofthe coating from the substrate at the intervention site upon stimulationof the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, wherein the device is adapted to dissociateat least a portion of the coating from the substrate at an interventionsite. In some embodiments, the device is adapted to dissociate theportion of the coating from the substrate at the intervention site uponstimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, wherein the device is adapted to dissociateat least a portion of the coating from the substrate and to deliver saidportion of the coating to an intervention site. In some embodiments, thedevice is adapted to deliver the portion of the coating to theintervention site upon stimulation of the coating.

In some embodiments of the methods and/or devices provided herein, thesubstrate comprises a balloon. In some embodiments, the portion of theballoon having coating thereon comprises an outer surface of theballoon. In some embodiments, the outer surface is a surface of theballoon exposed to a coating prior to balloon folding. In someembodiments, the outer surface is a surface of the balloon exposed to acoating following balloon folding. In some embodiments, the outersurface is a surface of the balloon exposed to a coating followingballoon crimping. In some embodiments, the coating comprises a materialthat undergoes plastic deformation at pressures provided by inflation ofthe balloon. In some embodiments, the coating comprises a material thatundergoes plastic deformation at a pressure that is less than the ratedburst pressure of the balloon.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a material that undergoes plastic deformation at apressure that is less than the nominal inflation pressure of theballoon. In some embodiments, the coating comprises a material thatundergoes plastic deformation with at least 8 ATM of pressure. In someembodiments, the coating comprises a material that undergoes plasticdeformation with at least 6 ATM of pressure. In some embodiments, thecoating comprises a material that undergoes plastic deformation with atleast 4 ATM of pressure. In some embodiments, the coating comprises amaterial that undergoes plastic deformation with at least 2 ATM ofpressure.

In some embodiments of the methods and/or devices provided herein, theballoon is a compliant balloon. In some embodiments, the balloon is asemi-compliant balloon. In some embodiments, the balloon is anon-compliant balloon. In some embodiments, the balloon conforms to ashape of the intervention site.

In some embodiments of the methods and/or devices provided herein, theballoon comprises a cylindrical portion. In some embodiments, theballoon comprises a substantially spherical portion. In someembodiments, the balloon comprises a complex shape. In some embodiments,the complex shape comprises at least one of a double noded shape, atriple noded shape, a waisted shape, an hourglass shape, and a ribbedshape.

In some embodiments of the methods and/or devices provided herein, thesubstrate comprises a cutting balloon. In some embodiments, the cuttingballoon comprises at least one tacking element adapted to tack thecoating to the intervention site. In some embodiments, the tackingelement is adapted to secure the coating to the cutting balloon untilinflation of the cutting balloon. In some embodiments, the tackingelement comprises a wire. In some embodiments, the wire is shaped in theform of an outward pointing wedge. In some embodiments, the tackingelement does not cut tissue at the intervention site.

In some embodiments of the methods and/or devices provided herein, thesubstrate comprises a biomedical implant. In some embodiments, thesubstrate comprises a surgical tool.

In some embodiments of the methods and/or devices provided herein, thesubstrate comprises at least one of a stent, a joint, a screw, a rod, apin, a plate, a staple, a shunt, a clamp, a clip, a suture, a sutureanchor, an electrode, a catheter, a lead, a graft, a dressing, apacemaker, a pacemaker housing, a cardioverter, a cardioverter housing,a defibrillator, a defibrillator housing, a prostheses, an ear drainagetube, an ophthalmic implant, an orthopedic device, a vertebral disk, abone substitute, an anastomotic device, a perivascular wrap, a colostomybag attachment device, a hemostatic barrier, a vascular implant, avascular support, a tissue adhesive, a tissue sealant, a tissuescaffold, and an intraluminal device.

In some embodiments of the methods and/or devices provided herein, thesubstrate comprises at least a portion of a tool for delivering to theintervention site a biomedical implant, wherein the substrate is thebiomedical implant or wherein the substrate is a portion of the devicethat is not the biomedical implant. In some embodiments, the substratecomprises at least a portion of a tool for performing a medicalprocedure. In some embodiments, the tool comprises at least one of: aknife, a scalpel, a guidewire, a guiding catheter, a introductioncatheter, a distracter, a needle, a syringe, a biopsy device, anarticulator, a Galotti articulator, a bone chisel, a bone crusher, acottle cartilage crusher, a bone cutter, a bone distractor, an Ilizarovapparatus, an intramedullary kinetic bone distractor, a bone drill, abone extender, a bone file, a bone lever, a bone mallet, a bone rasp, abone saw, a bone skid, a bone splint, a bone button, a caliper, acannula, a catheter, a cautery, a clamp, a coagulator, a curette, adepressor, a dilator, a dissecting knife, a distractor, a dermatome,forceps, dissecting forceps, tissue forceps, sponge forceps, boneforceps, Carmalt forceps, Cushing forceps, Dandy forceps, DeBakeyforceps, Doyen intestinal forceps, epilation forceps, Halstead forceps,Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, a hook, anerve hook, an obstetrical hook, a skin hook, a hypodermic needle, alancet, a luxator, a lythotome, a lythotript, a mallet, a partschmallet, a mouth prop, a mouth gag, a mammotome, a needle holder, anoccluder, an osteotome, an Epker osteotome, a periosteal elevator, aJoseph elevator, a Molt periosteal elevator, an Obweg periostealelevator, a septum elevator, a Tessier periosteal elevator, a probe, aretractor, a Senn retractor, a Gelpi retractor, a Weitlaner retractor, aUSA-Army/Navy retractor, an O'Connor-O'Sullivan retractor, a Deaverretractor, a Bookwalter retractor, a Sweetheart retractor, a Joseph skinhook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rakeretractor, a flexible rake retractor, a Ragnell retractor, aLinde-Ragnell retractor, a Davis retractor, a Volkman retractor, aMathieu retractor, a Jackson tracheal hook, a Crile retractor, aMeyerding finger retractor, a Little retractor, a Love Nerve retractor,a Green retractor, a Goelet retractor, a Cushing vein retractor, aLangenbeck retractor, a Richardson retractor, a Richardson-Eastmannretractor, a Kelly retractor, a Parker retractor, a Parker-Mottretractor, a Roux retractor, a Mayo-Collins retractor, a Ribbonretractor, an Alm retractor, a self retaining retractor, a Weitlanerretractor, a Beckman-Weitlaner retractor, a Beckman-Eaton retractor, aBeckman retractor, an Adson retractor, a rib spreader, a rongeur, ascalpel, an ultrasonic scalpel, a laser scalpel, scissors, irisscissors, Kiene scissors, Metzenbaum scissors, Mayo scissors, Tenotomyscissors, a spatula, a speculum, a mouth speculum, a rectal speculum,Sim's vaginal speculum, Cusco's vaginal speculum, a sternal saw, asuction tube, a surgical elevator, a surgical hook, a surgical knife,surgical mesh, a surgical needle, a surgical snare, a surgical sponge, asurgical spoon, a surgical stapler, a suture, a syringe, a tonguedepressor, a tonsillotome, a tooth extractor, a towel clamp, towelforceps, Backhaus towel forceps, Lorna towel forceps, a tracheotome, atissue expander, a subcutaneus inflatable balloon expander, a trephine,a trocar, tweezers, and a venous cliping.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the substrateusing a mechanical stimulation. In some embodiments, the coating isfreed from the substrate using a mechanical stimulation. In someembodiments, the coating is dissociated from the substrate using amechanical stimulation. In some embodiments, the coating is transferredfrom the substrate using a mechanical stimulation. In some embodiments,the coating is transferred to the intervention site using a mechanicalstimulation. In some embodiments, the coating is delivered to theintervention site using a mechanical stimulation. In some embodiments,the mechanical stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the mechanical stimulation is adapted to initiate thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the mechanical stimulation is adapted tocause the freeing, dissociation and/or transference of the coating fromthe substrate. In some embodiments, the mechanical stimulation comprisesat least one of a compressive force, a shear force, a tensile force, aforce exerted on the coating from a substrate side of the coating, aforce exerted on the coating by the substrate, a force exerted on thecoating from an external element, a translation, a rotation, avibration, and a combination thereof. In some embodiments, the externalelement is a part of the subject. In some embodiments, the externalelement is not part of the device. In some embodiments, the externalelement comprises a liquid. In some embodiments, the liquid is forcedbetween the coating and the substrate. In some embodiments, the liquidcomprises saline. In some embodiments, the liquid comprises water. Insome embodiments, the mechanical stimulation comprises a geometricconfiguration of the substrate that maximizes a shear force on thecoating. In some embodiments, the mechanical stimulation comprises ageometric configuration of the substrate that increases a shear force onthe coating. In some embodiments, the mechanical stimulation comprises ageometric configuration of the substrate that enhances a shear force onthe coating.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the substrateusing a chemical stimulation. In some embodiments, the coating is freedfrom the substrate using a chemical stimulation. In some embodiments,the coating is dissociated from the substrate using a chemicalstimulation. In some embodiments, the coating is transferred from thesubstrate using a chemical stimulation. In some embodiments, the coatingis transferred to the intervention site using a chemical stimulation. Insome embodiments, the coating is delivered to the intervention siteusing a chemical stimulation. In some embodiments, the chemicalstimulation comprises at least one of bulk degradation, interaction witha bodily fluid, interaction with a bodily tissue, a chemical interactionwith a non-bodily fluid, a chemical interaction with a chemical, anacid-base reaction, an enzymatic reaction, hydrolysis, and combinationsthereof. In some embodiments, the chemical stimulation comprises bulkdegradation of the coating. In some embodiments, the chemicalstimulation comprises interaction of the coating or a portion thereofwith a bodily fluid. In some embodiments, the chemical stimulationcomprises interaction of the coating or a portion thereof with a bodilytissue. In some embodiments, the chemical stimulation comprises achemical interaction of the coating or a portion thereof with anon-bodily fluid. In some embodiments, the chemical stimulationcomprises a chemical interaction of the coating or a portion thereofwith a chemical. In some embodiments, the chemical stimulation comprisesan acid-base reaction. In some embodiments, the chemical stimulationcomprises an enzymatic reaction. In some embodiments, the chemicalstimulation comprises hydrolysis.

In some embodiments of the methods and/or devices provided herein, thechemical stimulation is adapted to augment the freeing, dissociationand/or transference of the coating from the substrate. In someembodiments, the chemical stimulation is adapted to initiate thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the chemical stimulation is adapted tocause the freeing, dissociation and/or transference of the coating fromthe substrate. In some embodiments, the coating comprises a materialthat is adapted to transfer, free, and/or dissociate from the substratewhen at the intervention site in response to an in-situ enzymaticreaction resulting in a weak bond between the coating and the substrate.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the substrateusing a thermal stimulation. In some embodiments, the coating is freedfrom the substrate using a thermal stimulation. In some embodiments, thecoating is dissociated from the substrate using a thermal stimulation.In some embodiments, the coating is transferred from the substrate usinga thermal stimulation. In some embodiments, the coating is transferredto the intervention site using a thermal stimulation. In someembodiments, the coating is delivered to the intervention site using athermal stimulation. In some embodiments, the thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toaugment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the thermal stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the device by aelectromagnetic stimulation. In some embodiments, the coating is freedfrom the substrate using a electromagnetic stimulation. In someembodiments, the coating is dissociated from the substrate using aelectromagnetic stimulation. In some embodiments, the coating istransferred from the substrate using a electromagnetic stimulation. Insome embodiments, the coating is transferred to the intervention siteusing a electromagnetic stimulation. In some embodiments, the coating isdelivered to the intervention site using a electromagnetic stimulation.In some embodiments, the electromagnetic stimulation comprises anelectromagnetic wave comprising at least one of a radio wave, a microwave, a infrared wave, near infrared wave, a visible light wave, anultraviolet wave, a X-ray wave, and a gamma wave. In some embodiments,the electromagnetic stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the electromagnetic stimulation is adapted to initiatethe freeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the electromagnetic stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the device by asonic stimulation. In some embodiments, the coating is freed from thesubstrate using a sonic stimulation. In some embodiments, the coating isdissociated from the substrate using a sonic stimulation. In someembodiments, the coating is transferred from the substrate using a sonicstimulation. In some embodiments, the coating is transferred to theintervention site using a sonic stimulation. In some embodiments, thecoating is delivered to the intervention site using a sonic stimulation.In some embodiments, the sonic stimulation comprises a sound wave,wherein the sound wave is at least one of an ultrasound wave, anacoustic sound wave, and an infrasound wave. In some embodiments, thesonic stimulation is adapted to augment the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thesonic stimulation is adapted to initiate the freeing, dissociationand/or transference of the coating from the substrate. In someembodiments, the sonic stimulation is adapted to cause the freeing,dissociation and/or transference of the coating from the substrate.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the device by acombination of at least two of a mechanical stimulation, a chemicalstimulation, an electromagnetic stimulation, and a sonic stimulation.

In some embodiments of the methods and/or devices provided herein, thecoating is freed, dissociated, and/or transferred from the substrate byextrusion.

In some embodiments of the methods and/or devices provided herein, thedevice further comprises a release agent. In some embodiments, therelease agent is biocompatible. In some embodiments, the release agentis non-biocompatible. In some embodiments, the release agent comprises apowder. In some embodiments, the release agent comprises a lubricant. Insome embodiments, the release agent comprises a surface modification ofthe substrate.

In some embodiments of the methods and/or devices provided herein, therelease agent comprises a physical characteristic of the coating. Insome embodiments, the physical characteristic of the coating comprises apattern. In some embodiments, the pattern is a textured surface on thesubstrate side of the coating, wherein the substrate side of the coatingis the part of the coating on the substrate. In some embodiments, thepattern is a textured surface on the intervention site side of thecoating, wherein the intervention site side of the coating is the partof the coating that is transferred to, and/or delivered to, and/ordeposited at the intervention site.

In some embodiments of the methods and/or devices provided herein, therelease agent comprises a viscous fluid. In some embodiments, theviscous fluid comprises oil. In some embodiments, the viscous fluid is afluid that is viscous relative to water. In some embodiments, theviscous fluid is a fluid that is viscous relative to blood. In someembodiments, the viscous fluid is a fluid that is viscous relative tourine. In some embodiments, the viscous fluid is a fluid that is viscousrelative to bile. In some embodiments, the viscous fluid is a fluid thatis viscous relative to synovial fluid. In some embodiments, the viscousfluid is a fluid that is viscous relative to saline. In someembodiments, the viscous fluid is a fluid that is viscous relative to abodily fluid at the intervention site.

In some embodiments of the methods and/or devices provided herein, therelease agent comprises a gel.

In some embodiments of the methods and/or devices provided herein, therelease agent comprises at least one of the active agent and anotheractive agent. The active agent may be placed on the substrate prior tothe coating in order to act as the release agent. The active agent maybe a different active agent than the active agent in the coating. Theactive agent that is the release agent may provide for a second sourceof drug to be delivered to the intervention site or another locationonce the coating is released from (or transferred from, or freed from,or dissociated from) the substrate.

In some embodiments of the methods and/or devices provided herein, therelease agent comprises a physical characteristic of the substrate. Insome embodiments, the physical characteristic of the substrate comprisesat least one of a patterned coating surface and a ribbed coatingsurface. In some embodiments, the patterned coating surface comprises astent framework. In some embodiments, the ribbed coating surfacecomprises an undulating substrate surface. In some embodiments, theribbed coating surface comprises a substrate surface having bumpsthereon.

In some embodiments of the methods and/or devices provided herein, therelease agent comprises a property that is capable of changing at theintervention site. In some embodiments, the property comprises aphysical property. In some embodiments, the property comprises achemical property. In some embodiments, the release agent is capable ofchanging a property when in contact with at least one of a biologictissue and a biologic fluid. In some embodiments, the release agent iscapable of changing a property when in contact with an aqueous liquid.

In some embodiments of the methods and/or devices provided herein, therelease agent is between the substrate and the coating.

In some embodiments of the methods and/or devices provided herein,substantially all of the coating remains on said substrate until themedical device reaches the intervention site. In some embodiments, atleast about 10%, at least about 20%, at least about 30%, greater than35%, at least about 40%, between about 40% and about 45%, at least about50%, at least about 75%, at least about 85%, at least about 90%, atleast about 95%, and/or at least about 99% of the coating is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 10% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 20% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 30% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, greater than 35% of the coating is adapted totransfer from the substrate to the intervention site. In someembodiments, between about 40% and about 45%, of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 50% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 75% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 85% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 90% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 95% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 99% of the coating is adapted to transfer from the substrateto the intervention site. As used herein, “about” when used in referenceto a percentage of the coating can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of thecoating transferred, or as a variation of the percentage of the coatingtransferred).

In some embodiments of the methods and/or devices provided herein, thecoating portion that is adapted to transfer upon stimulation is on atleast one of a distal surface of the substrate, a middle surface of thesubstrate, a proximal surface of the substrate, and an abluminal surfaceof the substrate. In some embodiments, the stimulation decreases thecontact between the coating and the substrate. In some embodiments,device is adapted to transfer less than about 1%, less than about 5%,less than about 10%. less than about 15%, less than about 25%, about 35%or less, less than about 40%, less than about 50%, less than about 70%,less than about 80%, and/or less than about 90% of the coating absentstimulation of the coating.

In some embodiments of the methods and/or devices provided herein, atleast about 10%, at least about 20%, at least about 30%, greater than35%, at least about 40%, between about 40% and about 45%, at least about50%, at least about 75%, at least about 85%, at least about 90%, atleast about 95%, and/or at least about 99% of the active agent isadapted to transfer from the substrate to the intervention site. In someembodiments, at least about 10% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 20% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 30% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, greater than 35% of the active agent is adapted to transferfrom the substrate to the intervention site. In some embodiments,between about 40% and about 45%, of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 50% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 75% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 85% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 90% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 95% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 99% of the active agent is adapted totransfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the active agent canmean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as apercent of the percentage of the active agent transferred, or as avariation of the percentage of the active agent transferred).

In some embodiments of the methods and/or devices provided herein, theactive agent portion that is adapted to transfer upon stimulation is onat least one of a distal surface of the substrate, a middle surface ofthe substrate, a proximal surface of the substrate, and an abluminalsurface of the substrate. In some embodiments, the stimulation decreasesthe contact between the coating and the substrate. In some embodiments,the device is adapted to transfer less than about 1%, less than about5%, less than about 10%. less than about 15%, less than about 25%, about35% or less, less than about 40%, less than about 50%, less than about70%, less than about 80%, and/or less than about 90% of the active agentabsent stimulation of the coating.

In some embodiments of the methods and/or devices provided herein, thedevice is adapted to transfer at least about 10%, at least about 20%, atleast about 30%, greater than 35%, at least about 40%, between about 40%and about 45%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 10% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 20% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 30% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer greater than 35% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer between about 40% andabout 45%, of the coating from the substrate to the intervention site.In some embodiments, the device is adapted to transfer at least about50% of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 75% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 90% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 95% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating transferred, or as a variation of thepercentage of the coating transferred).

In some embodiments of the methods and/or devices provided herein, thecoating portion that transfers upon stimulation is on at least one of adistal surface of the substrate, a middle surface of the substrate, aproximal surface of the substrate, and an abluminal surface of thesubstrate. In some embodiments, stimulation decreases the contactbetween the coating and the substrate. In some embodiments, the deviceis adapted to transfer less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, about 35% or less,less than about 40%, less than about 50%, less than about 70%, less thanabout 80%, and/or less than about 90% of the coating absent stimulationof the coating.

In some embodiments of the methods and/or devices provided herein, thedevice is adapted to transfer at least about 10%, at least about 20%, atleast about 30%, greater than 35%, at least about 40%, between about 40%and about 45%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the active agent from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 10% of theactive agent from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 20% of theactive agent from the substrate to the intervention site. In someembodiments, the device is adapted to transfer at least about 30% of theactive agent from the substrate to the intervention site. In someembodiments, the device is adapted to transfer greater than 35% of theactive agent from the substrate to the intervention site. In someembodiments, the device is adapted to transfer between about 40% andabout 45%, of the active agent from the substrate to the interventionsite. In some embodiments, the device is adapted to transfer at leastabout 50% of the active agent from the substrate to the interventionsite. In some embodiments, the device is adapted to transfer at leastabout 75% of the active agent from the substrate to the interventionsite. In some embodiments, the device is adapted to transfer at leastabout 85% of the active agent from the substrate to the interventionsite. In some embodiments, the device is adapted to transfer at leastabout 90% of the active agent from the substrate to the interventionsite. In some embodiments, the device is adapted to transfer at leastabout 95% of the active agent from the substrate to the interventionsite. In some embodiments, the device is adapted to transfer at leastabout 99% of the active agent from the substrate to the interventionsite. As used herein, “about” when used in reference to a percentage ofthe active agent can mean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/orof 10%-50% (as a percent of the percentage of the active agenttransferred, or as a variation of the percentage of the active agenttransferred).

In some embodiments of the methods and/or devices provided herein, thecoating portion that transfers upon stimulation is on at least one of adistal surface of the substrate, a middle surface of the substrate, aproximal surface of the substrate, and an abluminal surface of thesubstrate. In some embodiments, the stimulation decreases the contactbetween the coating and the substrate. In some embodiments, the deviceis adapted to transfer less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, about 35% or less,less than about 40%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the active agent absent stimulation ofthe coating.

In some embodiments of the methods and/or devices provided herein, thedevice is adapted to free at least about 10%, at least about 20%, atleast about 30%, greater than 35%, at least about 40%, between about 40%and about 45%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating from the substrate. In some embodiments, the device isadapted to free at least about 10% of the coating from the substrate tothe intervention site. In some embodiments, the device is adapted tofree at least about 20% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted to free atleast about 30% of the coating from the substrate to the interventionsite. In some embodiments, the device is adapted to free greater than35% of the coating from the substrate. In some embodiments, the deviceis adapted to free between about 40% and about 45%, of the coating fromthe substrate. In some embodiments, the device is adapted to free atleast about 50% of the coating from the substrate to the interventionsite. In some embodiments, the device is adapted to free at least about75% of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 90% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 95% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating freed, or as a variation of thepercentage of the coating freed).

In some embodiments of the methods and/or devices provided herein, thecoating portion that frees upon stimulation is on at least one of adistal surface of the substrate, a middle surface of the substrate, aproximal surface of the substrate, and an abluminal surface of thesubstrate.

In some embodiments of the methods and/or devices provided herein, thestimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to free less than about 1%,less than about 5%, less than about 10%. less than about 15%, less thanabout 25%, about 35% or less, less than about 40%, less than about 50%,less than about 70%, less than about 80%, less than about 90% of thecoating absent stimulation of the coating.

In some embodiments of the methods and/or devices provided herein, thedevice is adapted to dissociate at least about 10%, at least about 20%,at least about 30%, greater than 35%, at least about 40%, between about40% and about 45%, at least about 50%, at least about 75%, at leastabout 85%, at least about 90%, at least about 95%, and/or at least about99% of the coating from the substrate. In some embodiments, the deviceis adapted to dissociate at least about 10% of the coating from thesubstrate to the intervention site. In some embodiments, the device isadapted to dissociate at least about 20% of the coating from thesubstrate to the intervention site. In some embodiments, the device isadapted to dissociate at least about 30% of the coating from thesubstrate to the intervention site. In some embodiments, the device isadapted to dissociate greater than 35% of the coating from thesubstrate. In some embodiments, the device is adapted to dissociatebetween about 40% and about 45%, of the coating from the substrate. Insome embodiments, the device is adapted to dissociate at least about 50%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 75% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 85% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 90% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 95% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 99% ofthe coating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating dissociated, or as a variation of thepercentage of the coating dissociated).

In some embodiments of the methods and/or devices provided herein, thecoating portion that dissociates upon stimulation is on at least one ofa distal surface of the substrate, a middle surface of the substrate, aproximal surface of the substrate, and an abluminal surface of thesubstrate. In some embodiments, stimulation decreases the contactbetween the coating and the substrate. In some embodiments, the deviceis adapted to dissociate less than about 1%, less than about 5%, lessthan about 10%. less than about 15%, less than about 25%, about 35% orless, less than about 40%, less than about 50%, less than about 70%,less than about 80%, less than about 90% of the coating absentstimulation of the coating.

In some embodiments of the methods and/or devices provided herein, thedevice is adapted to deliver at least about 10%, at least about 20%, atleast about 30%, greater than 35%, at least about 40%, between about 40%and about 45%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating to the intervention site. In some embodiments, the deviceis adapted to deliver at least about 10% of the coating to theintervention site. In some embodiments, the device is adapted to deliverat least about 20% of the coating to the intervention site. In someembodiments, the device is adapted to deliver at least about 30% of thecoating to the intervention site. In some embodiments, the device isadapted to deliver greater than 35% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver betweenabout 40% and about 45%, of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 50% ofthe coating to the intervention site. In some embodiments, the device isadapted to deliver at least about 75% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver at leastabout 85% of the coating to the intervention site. In some embodiments,the device is adapted to deliver at least about 90% of the coating tothe intervention site. In some embodiments, the device is adapted todeliver at least about 95% of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 99% ofthe coating to the intervention site. As used herein, “about” when usedin reference to a percentage of the coating can mean ranges of 1%-5%, of5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentage ofthe coating delivered, or as a variation of the percentage of thecoating delivered).

In some embodiments of the methods and/or devices provided herein, thecoating portion that is delivered upon stimulation is on at least one ofa distal surface of the substrate, a middle surface of the substrate, aproximal surface of the substrate, and an abluminal surface of thesubstrate. In some embodiments, the stimulation decreases the contactbetween the coating and the substrate. In some embodiments, the deviceis adapted to deliver less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, about 35% or less,less than about 40%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments of the methods and/or devices provided herein, theactive agent comprises a pharmaceutical agent.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises a macrolide immunosuppressive drug. Insome embodiments the macrolide immunosuppressive drug comprises one ormore of rapamycin, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 4O—O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin4O—O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,4O—O-(2-Acetoxy)ethyl-rapamycin 4O—O-(2-Nicotinoyloxy)ethyl-rapamycin,4O—O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin4O—O—(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,4O—O-(2-Aminoethyl)-rapamycin, 4O—O-(2-Acetaminoethyl)-rapamycin4O—O-(2-Nicotinamidoethyl)-rapamycin,4O—O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,4O—O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent is agent is selected form the group consisting ofIn some embodiments, a pharmaceutical agent is at least one of:Acarbose, acetylsalicylic acid, acyclovir, allopurinol, alprostadil,prostaglandins, amantadine, ambroxol, amlodipine, S-aminosalicylic acid,amitriptyline, atenolol, azathioprine, balsalazide, beclomethasone,betahistine, bezafibrate, diazepam and diazepam derivatives, budesonide,bufexamac, buprenorphine, methadone, calcium salts, potassium salts,magnesium salts, candesartan, carbamazepine, captopril, cetirizine,chenodeoxycholic acid, theophylline and theophylline derivatives,trypsins, cimetidine, clobutinol, clonidine, cotrimoxazole, codeine,caffeine, vitamin D and derivatives of vitamin D, colestyramine,cromoglicic acid, coumarin and coumarin derivatives, cysteine,ciclosporin, cyproterone, cytabarine, dapiprazole, desogestrel,desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate,dimethyl sulphoxide, dimeticone, domperidone and domperidan derivatives,dopamine, doxazosin, doxylamine, benzodiazepines, diclofenac,desipramine, econazole, ACE inhibitors, enalapril, ephedrine,epinephrine, epoetin and epoetin derivatives, morphinans, calciumantagonists, modafinil, orlistat, peptide antibiotics, phenytoin,riluzoles, risedronate, sildenafil, topiramate, estrogen, progestogenand progestogen derivatives, testosterone derivatives, androgen andandrogen derivatives, ethenzamide, etofenamate, etofibrate, fenofibrate,etofylline, famciclovir, famotidine, felodipine, fentanyl,fenticonazole, gyrase inhibitors, fluconazole, fluarizine, fluoxetine,flurbiprofen, ibuprofen, fluvastatin, follitropin, formoterol,fosfomicin, furosemide, fusidic acid, gallopamil, ganciclovir,gemfibrozil, ginkgo, Saint John's wort, glibenclamide, urea derivativesas oral antidiabetics, glucagon, glucosamine and glucosaminederivatives, glutathione, glycerol and glycerol derivatives,hypothalamus hormones, guanethidine, halofantrine, haloperidol, heparin(and derivatives), hyaluronic acid, hydralazine, hydrochlorothiazide(and derivatives), salicylates, hydroxyzine, imipramine, indometacin,indoramine, insulin, iodine and iodine derivatives, isoconazole,isoprenaline, glucitol and glucitol derivatives, itraconazole,ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa,levomethadone, thyroid hormones, lipoic acid (and derivatives),lisinopril, lisuride, lofepramine, loperamide, loratadine, maprotiline,mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine,meloxicam, mepindolol, meprobamate, mesalazine, mesuximide, metamizole,metformin, methylphenidate, metixene, metoprolol, metronidazole,mianserin, miconazole, minoxidil, misoprostol, mizolastine, moexipril,morphine and morphine derivatives, evening primrose, nalbuphine,naloxone, tilidine, naproxen, narcotine, natamycin, neostigmine,nicergoline, nicethamide, nifedipine, niflumic acid, nimodipine,nimorazole, nimustine, nisoldipine, adrenaline and adrenalinederivatives, novamine sulfone, noscapine, nystatin, olanzapine,olsalazine, omeprazole, omoconazole, oxaceprol, oxiconazole,oxymetazoline, pantoprazole, paracetamol (acetaminophen), paroxetine,penciclovir, pentazocine, pentifylline, pentoxifylline, perphenazine,pethidine, plant extracts, phenazone, pheniramine, barbituric acidderivatives, phenylbutazone, pimozide, pindolol, piperazine, piracetam,pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin,procaine, promazine, propiverine, propranolol, propyphenazone,protionamide, proxyphylline, quetiapine, quinapril, quinaprilat,ramipril, ranitidine, reproterol, reserpine, ribavirin, risperidone,ritonavir, ropinirole, roxatidine, ruscogenin, rutoside (andderivatives), sabadilla, salbutamol, salmeterol, scopolamine,selegiline, sertaconazole, sertindole, sertralion, silicates,simvastatin, sitosterol, sotalol, spaglumic acid, spirapril,spironolactone, stavudine, streptomycin, sucralfate, sufentanil,sulfasalazine, sulpiride, sultiam, sumatriptan, suxamethonium chloride,tacrine, tacrolimus, taliolol, taurolidine, temazepam, tenoxicam,terazosin, terbinafine, terbutaline, terfenadine, terlipressin,tertatolol, teryzoline, theobromine, butizine, thiamazole,phenothiazines, tiagabine, tiapride, propionic acid derivatives,ticlopidine, timolol, tinidazole, tioconazole, tioguanine, tioxolone,tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate,tolperisone, topotecan, torasemide, tramadol, tramazoline, trandolapril,tranylcypromine, trapidil, trazodone, triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimipramine, tripelennamine,triprolidine, trifosfamide, tromantadine, trometamol, tropalpin,troxerutine, tulobuterol, tyramine, tyrothricin, urapidil, valaciclovir,valproic acid, vancomycin, vecuronium chloride, Viagra, venlafaxine,verapamil, vidarabine, vigabatrin, viloazine, vincamine, vinpocetine,viquidil, warfarin, xantinol nicotinate, xipamide, zafirlukast,zalcitabine, zidovudine, zolmitriptan, zolpidem, zoplicone, zotipine,amphotericin B, caspofungin, voriconazole, resveratrol, PARP-1inhibitors (including imidazoquinolinone, imidazpyridine, andisoquinolindione, tissue plasminogen activator (tPA), melagatran,lanoteplase, reteplase, staphylokinase, streptokinase, tenecteplase,urokinase, abciximab (ReoPro), eptifibatide, tirofiban, prasugrel,clopidogrel, dipyridamole, cilostazol, VEGF, heparan sulfate,chondroitin sulfate, elongated “RGD” peptide binding domain, CD34antibodies, cerivastatin, etorvastatin, losartan, valartan,erythropoietin, rosiglitazone, pioglitazone, mutant protein Apo A1Milano, adiponectin, (NOS) gene therapy, glucagon-like peptide 1,atorvastatin, and atrial natriuretic peptide (ANP), lidocaine,tetracaine, dibucaine, hyssop, ginger, turmeric, Arnica montana,helenalin, cannabichromene, rofecoxib, hyaluronidase, and salts,derivatives, isomers, racemates, diastereoisomers, prodrugs, hydrate,ester, or analogs thereof.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises hyaluronidase.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises cilostazol.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises dipyridamole.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises an antibiotic agent.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent comprises a chemotherapeutic agent.

In some embodiments of the methods and/or devices provided herein, thepharmaceutical agent is in a therapeutically desirable morphology.

In some embodiments of the methods and/or devices provided herein, theactive agent comprises a chemotherapeutic agent. In some embodiments ofthe methods and/or devices provided herein, the pharmaceutical agentcomprises a chemotherapeutic agent. In some embodiments, thechemotherapeutic agent comprises at least one of: an angiostatin, DNAtopoisomerase, endostatin, genistein, ornithine decarboxylaseinhibitors, chlormethine, melphalan, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine (BCNU), streptozocin,6-mercaptopurine, 6-thioguanine, Deoxyco-formycin, IFN-α,17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone,fluoxymesterone, dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyl-testosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, estramustine,medroxyprogesteroneacetate, flutamide, zoladex, mitotane,hexamethylmelamine, indolyl-3-glyoxylic acid derivatives, (e.g.,indibulin), doxorubicin and idarubicin, plicamycin (mithramycin) andmitomycin, mechlorethamine, cyclophosphamide analogs,trazenes-dacarbazinine (DTIC), pentostatin and 2-chlorodeoxyadenosine,letrozole, camptothecin (and derivatives), navelbine, erlotinib,capecitabine, acivicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, ambomycin, ametantrone acetate, anthramycin, asperlin,azacitidine, azetepa, azotomycin, batimastat, benzodepa, bisnafide,bisnafide dimesylate, bizelesin, bropirimine, cactinomycin, calusterone,carbetimer, carubicin hydrochloride, carzelesin, cedefingol, celecoxib(COX-2 inhibitor), cirolemycin, crisnatol mesylate, decitabine,dexormaplatin, dezaguanine mesylate, diaziquone, duazomycin, edatrexate,eflomithine, elsamitrucin, enloplatin, enpromate, epipropidine,erbulozole, etanidazole, etoprine, flurocitabine, fosquidone,lometrexol, losoxantrone hydrochloride, masoprocol, maytansine,megestrol acetate, melengestrol acetate, metoprine, meturedepa,mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitosper,mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran,pegaspargase, peliomycin, pentamustine, perfosfamide, piposulfan,plomestane, porfimer sodium, porfiromycin, puromycin, pyrazofurin,riboprine, safingol, simtrazene, sparfosate sodium, spiromustine,spiroplatin, streptonigrin, sulofenur, tecogalan sodium, taxotere,tegafur, teloxantrone hydrochloride, temoporfin, thiamiprine,tirapazamine, trestolone acetate, triciribine phosphate, trimetrexateglucuronate, tubulozole hydrochloride, uracil mustard, uredepa,verteporfin, vinepidine sulfate, vinglycinate sulfate, vinleurosinesulfate, vinorelbine tartrate, vinrosidine sulfate, zeniplatin,zinostatin, 20-epi-1,25 dihydroxyvitamin D3, 5-ethynyluracil,acylfulvene, adecypenol, ALL-TK antagonists, ambamustine, amidox,amifostine, aminolevulinic acid, amrubicin, anagrelide, andrographolide,antagonist D, antagonist G, antarelix, anti-dorsalizing morphogeneticprotein-1, antiandrogen, antiestrogen, estrogen agonist, apurinic acid,ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane,atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron,azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR/ABLantagonists, benzochlorins, benzoylstaurosporine, beta lactamderivatives, beta-alethine, betaclamycin B, betulinic acid, bFGFinhibitor, bisaziridinylspermine, bistratene A, breflate, buthioninesulfoximine, calcipotriol, calphostin C, carboxamide-amino-triazole,carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived inhibitor,casein kinase inhibitors (ICOS), castanospermine, cecropin B,cetrorelix, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin,clomifene analogues, clotrimazole, collismycin A, collismycin B,combretastatin A4, combretastatin analogue, conagenin, crambescidin 816,cryptophycin 8, cryptophycin A derivatives, curacin A,cyclopentanthraquinones, cycloplatam, cypemycin, cytolytic factor,cytostatin, dacliximab, dehydrodidemnin B, dexamethasone, dexifosfamide,dexrazoxane, dexverapamil, didemnin B, didox, diethylnorspermine,dihydro-5-azacytidine, dihydrotaxol, 9-, dioxamycin, docosanol,dolasetron, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine,edrecolomab, elemene, emitefur, estramustine analogue, filgrastim,flavopiridol, flezelastine, fluasterone, fluorodaunorunicinhydrochloride, forfenimex, gadolinium texaphyrin, galocitabine,gelatinase inhibitors, glutathione inhibitors, hepsulfam, heregulin,hexamethylene bisacetamide, hypericin, ibandronic acid, idramantone,ilomastat, imatinib (e.g., Gleevec), imiquimod, immunostimulantpeptides, insulin-like growth factor-1 receptor inhibitor, interferonagonists, interferons, interleukins, iobenguane, iododoxorubicin,ipomeanol, 4-, iroplact, irsogladine, isobengazole, isohomohalicondrinB, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate,leinamycin, lenograstim, lentinan sulfate, leptolstatin, leukemiainhibiting factor, leukocyte alpha interferon,leuprolide+estrogen+progesterone, linear polyamine analogue, lipophilicdisaccharide peptide, lipophilic platinum compounds, lissoclinamide 7,lobaplatin, lombricine, loxoribine, lurtotecan, lutetium texaphyrin,lysofylline, lytic peptides, maitansine, mannostatin A, marimastat,maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors,meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone,miltefosine, mirimostim, mitoguazone, mitotoxin fibroblast growthfactor-saporin, mofarotene, molgramostim, Erbitux, human chorionicgonadotrophin, monophosphoryl lipid A+myobacterium cell wall sk, mustardanticancer agent, mycaperoxide B, mycobacterial cell wall extract,myriaporone, N-acetyldinaline, N-substituted benzamides, nagrestip,naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin,nemorubicin, neridronic acid, nisamycin, nitric oxide modulators,nitroxide antioxidant, nitrullyn, oblimersen (Genasense),O⁶-benzylguanine, okicenone, onapristone, ondansetron, oracin, oralcytokine inducer, paclitaxel analogues and derivatives, palauamine,palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifene, parabactin,peldesine, pentosan polysulfate sodium, pentrozole, perflubron, perillylalcohol, phenazinomycin, phenylacetate, phosphatase inhibitors,picibanil, pilocarpine hydrochloride, placetin A, placetin B,plasminogen activator inhibitor, platinum complex, platinum compounds,platinum-triamine complex, propyl bis-acridone, prostaglandin J2,proteasome inhibitors, protein A-based immune modulator, protein kinaseC inhibitors, microalgal, pyrazoloacridine, pyridoxylated hemoglobinpolyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, rasfarnesyl protein transferase inhibitors, ras-GAP inhibitor, retelliptinedemethylated, rhenium Re 186 etidronate, ribozymes, RII retinamide,rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saintopin,SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetics, senescence derivedinhibitor 1, signal transduction inhibitors, sizofiran, sobuzoxane,sodium borocaptate, solverol, somatomedin binding protein, sonermin,sparfosic acid, spicamycin D, splenopentin, spongistatin 1, squalamine,stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactiveintestinal peptide antagonist, suradista, suramin, swainsonine,tallimustine, tazarotene, tellurapyrylium, telomerase inhibitors,tetrachlorodecaoxide, tetrazomine, thiocoraline, thrombopoietin,thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist,thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin,titanocene bichloride, topsentin, translation inhibitors, tretinoin,triacetyluridine, tropisetron, turosteride, ubenimex, urogenitalsinus-derived growth inhibitory factor, variolin B, velaresol, veramine,verdins, vinxaltine, vitaxin, zanoterone, zilascorb, zinostatinstimalamer, acanthifolic acid, aminothiadiazole, anastrozole,bicalutamide, brequinar sodium, capecitabine, carmofur, Ciba-GeigyCGP-30694, cladribine, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, cytarabine ocfosfate, Lilly DATHF,Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox,Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015,fazarabine, floxuridine, fludarabine, fludarabine phosphate,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152,5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011, LillyLY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine,nolvadex, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi ChemicalPL-AC, stearate, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF,trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinaseinhibitors, Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamideanalogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207,bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine(BiCNU), Chinoin-139, Chinoin-153, chlorambucil, cisplatin,cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate,dacarbazine, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Chugai DWA-2114R, ITI E09,elmustine, Erbamont FCE-24517, estramustine phosphate sodium, etoposidephosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam,ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol,mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, thiotepa, Yakult Honsha SN-22,spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol, Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative,Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins,anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B,Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b,Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitomycinanalogues, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon KayakuNK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine,oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin,pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin,sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow BrandSN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SSPharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B,Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine,tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405,Yoshitomi Y-25024, zorubicin, 5-fluorouracil (5-FU), the peroxidateoxidation product of inosine, adenosine, or cytidine with methanol orethanol, cytosine arabinoside (also referred to as Cytarabin, araC, andCytosar), 5-Azacytidine, 2-Fluoroadenosine-5′-phosphate (Fludara, alsoreferred to as FaraA), 2-Chlorodeoxyadenosine, Abarelix, Abbott A-84861,Abiraterone acetate, Aminoglutethimide, Asta Medica AN-207, Antide,Chugai AG-041R, Avorelin, aseranox, Sensus B2036-PEG, buserelin, BTGCB-7598, BTG CB-7630, Casodex, cetrolix, clastroban, clodronatedisodium, Cosudex, Rotta Research CR-1505, cytadren, crinone,deslorelin, droloxifene, dutasteride, Elimina, Laval University EM-800,Laval University EM-652, epitiostanol, epristeride, Mediolanum EP-23904,EntreMed 2-ME, exemestane, fadrozole, finasteride, formestane, Pharmacia& Upjohn FCE-24304, ganirelix, goserelin, Shire gonadorelin agonist,Glaxo Wellcome GW-5638, Hoechst Marion Roussel Hoe-766, NCI hCG,idoxifene, isocordoin, Zeneca ICI-182780, Zeneca ICI-118630, TulaneUniversity J015X, Schering Ag J96, ketanserin, lanreotide, MilkhausLDI-200, letrozol, leuprolide, leuprorelin, liarozole, lisuride hydrogenmaleate, loxiglumide, mepitiostane, Ligand Pharmaceuticals LG-1127,LG-1447, LG-2293, LG-2527, LG-2716, Bone Care International LR-103,Lilly LY-326315, Lilly LY-353381-HCl, Lilly LY-326391, Lilly LY-353381,Lilly LY-357489, miproxifene phosphate, Orion Pharma MPV-2213ad, TulaneUniversity MZ-4-71, nafarelin, nilutamide, Snow Brand NKS01, Azko NobelORG-31710, Azko Nobel ORG-31806, orimeten, orimetene, orimetine,ormeloxifene, osaterone, Smithkline Beecham SKB-105657, Tokyo UniversityOSW-1, Peptech PTL-03001, Pharmacia & Upjohn PNU-156765, quinagolide,ramorelix, Raloxifene, statin, sandostatin LAR, Shionogi S-10364,Novartis SMT-487, somavert, somatostatin, tamoxifen, tamoxifenmethiodide, teverelix, toremifene, triptorelin, TT-232, vapreotide,vorozole, Yamanouchi YM-116, Yamanouchi YM-511, Yamanouchi YM-55208,Yamanouchi YM-53789, Schering AG ZK-1911703, Schering AG ZK-230211, andZeneca ZD-182780, alpha-carotene, alpha-difluoromethyl-arginine,acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10,antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplastonAS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol,baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015,bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide,Wellcome BW-502, Wellcome BW-773, calcium carbonate, Calcet, Calci-Chew,Calci-Mix, Roxane calcium carbonate tablets, caracemide, carmethizolehydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053,Chemex CHX-100, Warn er-Lambert CI-921, Warner-Lambert CI-937,Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone,ICN compound 1259, ICN compound 4711, Contracan, Cell Pathways CP-461,Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine,cytocytin, Merz D-609, DABIS maleate, datelliptinium, DFMO, didemnin-B,dihaematoporphyrin ether, dihydrolenperone dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel,Encore Pharmaceuticals E7869, elliprabin, elliptinium acetate, TsumuraEPMTC, ergotamine, etoposide, etretinate, Eulexin, Cell PathwaysExisulind (sulindac sulphone or CP-246), fenretinide, Florical, FujisawaFR-57704, gallium nitrate, gemcitabine, genkwadaphnin, Gerimed, ChugaiGLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, GreenCross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine,irinotecan, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477,ketoconazole, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110,American Cyanamid L-623, leucovorin, levamisole, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP,marycin, Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone,merocyanine derivatives, methylanilinoacridine, Molecular GeneticsMGI-136, minactivin, mitonafide, mitoquidone, Monocal, mopidamol,motretinide, Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids,Nilandron, Nisshin Flour Milling N-021, N-acylated-dehydroalanines,nafazatrom, Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative,Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCINSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, retinoids, R-flurbiprofen(Encore Pharmaceuticals), Sandostatin, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, Scherring-Plough SC-57050, Scherring-PloughSC-57068, selenium (selenite and selenomethionine), SmithKlineSK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol,spirocyclopropane derivatives, spirogermanium, Unimed, SS PharmaceuticalSS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071,Sugen SU-101, Sugen SU-5416, Sugen SU-6668, sulindac, sulindac sulfone,superoxide dismutase, Toyama T-506, Toyama T-680, taxol, TeijinTEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol,Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028,ukrain, Eastman Kodak USB-006, vinblastine, vinblastine sulfate,vincristine, vincristine sulfate, vindesine, vindesine sulfate,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides,Yamanouchi YM-534, Zileuton, ursodeoxycholic acid, Zanosar.

In some embodiments of the methods and/or devices provided herein, thechemotherapeutic agent comprises Bacillus Calmette-Guerin (BCG).

In some embodiments of the methods and/or devices provided herein, theactive agent comprises an antibiotic agent. In some embodiments of themethods and/or devices provided herein, the pharmaceutical agentcomprises an antibiotic agent. In some embodiments, the antibiotic agentcomprises at least one of: amikacin, amoxicillin, gentamicin, kanamycin,neomycin, netilmicin, paromomycin, tobramycin, geldanamycin, herbimycin,carbacephem (loracarbef), ertapenem, doripenem, imipenem, cefadroxil,cefazolin, cefalotin, cephalexin, cefaclor, cefamandole, cefoxitin,cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone,cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime,ceftriaxone, cefepime, ceftobiprole, clarithromycin, clavulanic acid,clindamycin, teicoplanin, azithromycin, dirithromycin, erythromycin,troleandomycin, telithromycin, aztreonam, ampicillin, azlocillin,bacampicillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, mezlocillin, meticillin, nafcillin, norfloxacin,oxacillin, penicillin G, penicillin V, piperacillin, pvampicillin,pivmecillinam, ticarcillin, bacitracin, colistin, polymyxin B,ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin,moxifloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin,afenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide,sulfamethoxazole, sulfisoxazole, trimethoprim,trimethoprim-sulfamethoxazole, demeclocycline, doxycycline,oxytetracycline, tetracycline, arsphenamine, chloramphenicol,lincomycin, ethambutol, fosfomycin, furazolidone, isoniazid, linezolid,mupirocin, nitrofurantoin, platensimycin, pyrazinamide,quinupristin/dalfopristin, rifampin, thiamphenicol, rifampicin,minocycline, sultamicillin, sulbactam, sulphonamides, mitomycin,spectinomycin, spiramycin, roxithromycin, and meropenem.

In some embodiments of the methods and/or devices provided herein, theantibiotic agent comprises erythromycin.

In some embodiments of the methods and/or devices provided herein, theactive agent comprises an active biological agent. In some embodiments,the active biological agent comprises an active secondary, tertiary orquaternary structure. In some embodiments, the active biological agentcomprises at least one of growth factors, cytokines, peptides, proteins,enzymes, glycoproteins, nucleic acids, antisense nucleic acids, fattyacids, antimicrobials, vitamins, hormones, steroids, lipids,polysaccharides, carbohydrates, a hormone, gene therapies, RNA, siRNA,and/or cellular therapies such as stem cells and/or T-cells.

In some embodiments of the methods and/or devices provided herein, theactive biological agent comprises siRNA.

In some embodiments of the methods and/or devices provided herein, thecoating further comprises a polymer. In some embodiments, the activeagent comprises a polymer. In some embodiments, the polymer comprises atleast one of polyalkyl methacrylates, polyalkylene-co-vinyl acetates,polyalkylenes, polyurethanes, polyanhydrides, aliphatic polycarbonates,polyhydroxyalkanoates, silicone containing polymers, polyalkylsiloxanes, aliphatic polyesters, polyglycolides, polylactides,polylactide-co-glycolides, poly(e-caprolactone)s,polytetrahalooalkylenes, polystyrenes, poly(phosphasones), copolymersthereof, and combinations thereof.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a bioabsorbable polymer. In some embodiments, theactive agent comprises a bioabsorbable polymer. In some embodiments, thebioabsorbable polymer comprises at least one of: Polylactides (PLA);PLGA (poly(lactide-co-glycolide)); Polyanhydrides; Polyorthoesters;Poly(N-(2-hydroxypropyl) methacrylamide); DLPLA—poly(dl-lactide);LPLA—poly(1-lactide); PGA-polyglycolide; PDO—poly(dioxanone);PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC-poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations, copolymers, and derivatives thereof. In some embodiments,the bioabsorbable polymer comprises between 1% and 95% glycolic acidcontent PLGA-based polymer.

In some embodiments of the methods and/or devices provided herein, thepolymer comprises at least one of polycarboxylic acids, cellulosicpolymers, proteins, polypeptides, polyvinylpyrrolidone, maleic anhydridepolymers, polyamides, polyvinyl alcohols, polyethylene oxides,glycosaminoglycans, polysaccharides, polyesters, aliphatic polyesters,polyurethanes, polystyrenes, copolymers, silicones, silicone containingpolymers, polyalkyl siloxanes, polyorthoesters, polyanhydrides,copolymers of vinyl monomers, polycarbonates, polyethylenes,polypropytenes, polylactic acids, polylactides, polyglycolic acids,polyglycolides, polylactide-co-glycolides, polycaprolactones,poly(e-caprolactone)s, polyhydroxybutyrate valerates, polyacrylamides,polyethers, polyurethane dispersions, polyacrylates, acrylic latexdispersions, polyacrylic acid, polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, aliphatic polycarbonatespolyhydroxyalkanoates, polytetrahalooalkylenes, poly(phosphasones),polytetrahalooalkylenes, poly(phosphasones), and mixtures, combinations,and copolymers thereof. The polymers of the present invention may benatural or synthetic in origin, including gelatin, chitosan, dextrin,cyclodextrin, Poly(urethanes), Poly(siloxanes) or silicones,Poly(acrylates) such as [rho]oly(methyl methacrylate), poly(butylmethacrylate), and Poly(2-hydroxy ethyl methacrylate), Poly(vinylalcohol) Poly(olefins) such as poly(ethylene), [rho]oly(isoprene),halogenated polymers such as Poly(tetrafluoroethylene)—and derivativesand copolymers such as those commonly sold as Teflon® products,Poly(vinylidine fluoride), Poly(vinyl acetate), Poly(vinyl pyrrolidone),Poly(acrylic acid), Polyacrylamide, Poly(ethylene-co-vinyl acetate),Poly(ethylene glycol), Poly(propylene glycol), Poly(methacrylic acid);etc. Suitable polymers also include absorbable and/or resorbablepolymers including the following, combinations, copolymers andderivatives of the following: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(1-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

In some embodiments of the methods and/or devices provided herein, thepolymer has a dry modulus between 3,000 and 12,000 KPa. In someembodiments, the polymer is capable of becoming soft after implantation.In some embodiments, the polymer is capable of becoming soft afterimplantation by hydration, degradation or by a combination of hydrationand degradation. In some embodiments, the polymer is adapted totransfer, free, and/or dissociate from the substrate when at theintervention site due to hydrolysis of the polymer.

In some embodiments of the methods and/or devices provided herein, thebioabsorbable polymer is capable of resorbtion in at least one of: about1 day, about 3 days, about 5 days, about 7 days, about 14 days, about 3weeks, about 4 weeks, about 45 days, about 60 days, about 90 days, about180 days, about 6 months, about 9 months, about 1 year, about 1 to about2 days, about 1 to about 5 days, about 1 to about 2 weeks, about 2 toabout 4 weeks, about 45 to about 60 days, about 45 to about 90 days,about 30 to about 90 days, about 60 to about 90 days, about 90 to about180 days, about 60 to about 180 days, about 180 to about 365 days, about6 months to about 9 months, about 9 months to about 12 months, about 9months to about 15 months, and about 1 year to about 2 years.

In some embodiments of the methods and/or devices provided herein, atleast a portion of the substrate is bioabsorbable. In some embodiments,the substrate comprises at least one of a bioabsorbable polymer and abioabsorbable metal. In some embodiments, the at least one bioabsorbablepolymer or bioabsorbable metal is capable of resorbtion in at least oneof: about 1 day, about 3 days, about 5 days, about 7 days, about 14days, about 3 weeks, about 4 weeks, about 45 days, about 60 days, about90 days, about 180 days, about 6 months, about 9 months, about 1 year,about 1 to about 2 days, about 1 to about 5 days, about 1 to about 2weeks, about 2 to about 4 weeks, about 45 to about 60 days, about 45 toabout 90 days, about 30 to about 90 days, about 60 to about 90 days,about 90 to about 180 days, about 60 to about 180 days, about 180 toabout 365 days, about 6 months to about 9 months, about 9 months toabout 12 months, about 9 months to about 15 months, and about 1 year toabout 2 years.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a hydrogel. In some embodiments, the hydrogel isadapted to degrade by bulk degradation. In some embodiments, thehydrogel is adapted to degrade by surface degradation.

In some embodiments of the methods and/or devices provided herein, thecoating comprises laminated layers that allow direct control of thetransfer, freeing, and/or dissociation of the coating from thesubstrate. In some embodiments, the coating comprises laminated layersthat allow direct control of the transferring, freeing, depositing,tacking, and/or dissociating of the coating from the substrate, whereinat least one of the layers comprises the active agent. In someembodiments, the coating comprises laminated layers that allow directcontrol of the transferring, freeing, depositing, tacking, and/ordissociating of the coating from the substrate, wherein at least one ofthe layers comprises the pharmaceutical agent.

In some embodiments of the methods and/or devices provided herein, thecoating further comprises at least one image enhanced polymer. In someembodiments, the image enhanced polymer comprises at least one of:EgadMe in which a galactopyranose ring is synthesized to protect aGd(III) ion from bulk water; a conjugated polymer MEH-PPV nanoparticle;bismuth trioxide; a near infrared (NIR) fluorochrome; a bioluminescenceagent; a SPECT radionuclide; gadolinium diethylenetriamine pentaaceticacid; Echo-Coat, an ultrasound imaging agent (STS-Biopolymers); andbarium sulfate. In some embodiments, the coating comprises an imagingagent. In some embodiments, the imaging agent comprises at least one ofa barium compound and an iodine compound.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a biodegradable material that is adhered and/orcohered to the substrate prior to implantation, wherein thebiodegradable material is capable of degrading over time to lose itscohesion and/or adhesion to the substrate. In some embodiments, thepharmaceutical agent and/or the active agent is released from thecoating within at least one of about 1 day, about 3 days, about 5 days,about 7 days, about 14 days, about 3 weeks, about 4 weeks, about 45days, about 60 days, about 90 days, about 180 days, about 6 months,about 9 months, about 1 year, about 1 to about 2 days, about 1 to about5 days, about 1 to about 2 weeks, about 2 to about 4 weeks, about 45 toabout 60 days, about 45 to about 90 days, about 30 to about 90 days,about 60 to about 90 days, about 90 to about 180 days, about 60 to about180 days, about 180 to about 365 days, about 6 months to about 9 months,about 9 months to about 12 months, about 9 months to about 15 months,and about 1 year to about 2 years.

In some embodiments of the methods and/or devices provided herein, thecoating is prepared by a solvent based coating method. In someembodiments, the coating is prepared by a solvent plasma based coatingmethod.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a microstructure. In some embodiments, particles ofthe active agent are sequestered or encapsulated within saidmicrostructure. In some embodiments, the microstructure comprisesmicrochannels, micropores and/or microcavities. In some embodiments, themicrostructure is selected to allow sustained release of the activeagent. In some embodiments, the microstructure is selected to allowcontrolled release of the active agent.

In some embodiments of the methods and/or devices provided herein, thecoating is formed on said substrate by a process comprising depositing apolymer and/or the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess. In some embodiments of the methods and/or devices providedherein, wherein the coating is formed on said substrate by a processcomprising at least one of: depositing a polymer by an e-RESS, ane-SEDS, or an e-DPC process, and depositing the pharmaceutical agent byan e-RESS, an e-SEDS, or an e-DPC process. In some embodiments of themethods and/or devices provided herein, the coating is formed on saidsubstrate by a process comprising at least one of: depositing a polymerby an e-RESS, an e-SEDS, or an e-DPC process, and depositing the activeagent by an e-RESS, an e-SEDS, or an e-DPC process. In some embodiments,the process of forming said coating provides improved adherence of thecoating to the substrate prior to deployment of the device at theintervention site and facilitates dissociation of said coating from saidsubstrate at the intervention site. In some embodiments, the coating isformed on said substrate by a process comprising depositing the activeagent by an e-RESS, an e-SEDS, or an e-DPC process without electricallycharging the substrate. In some embodiments, the coating is formed onsaid substrate by a process comprising depositing the active agent onthe substrate by an e-RESS, an e-SEDS, or an e-DPC process withoutcreating an electrical potential between the substrate and a coatingapparatus used to deposit the coating.

In some embodiments of the methods and/or devices provided herein, theintervention site is in or on the body of a subject. In someembodiments, the intervention site is a vascular wall. In someembodiments, the intervention site is a non-vascular lumen wall. In someembodiments, the intervention site is a vascular cavity wall.

In some embodiments of the methods and/or devices provided herein, theintervention site is a wall of a body cavity. In some embodiments, thebody cavity is the result of a lumpectomy. In some embodiments, theintervention site is a cannulized site within a subject.

In some embodiments of the methods and/or devices provided herein, theintervention site is a sinus wall. In some embodiments, the interventionsite is a sinus cavity wall. In some embodiments, the active agentcomprises a corticosteroid.

In some embodiments of the methods and/or devices provided herein, theintervention site is located in the reproductive system of a subject. Insome embodiments, the device is adapted to aid in fertility. In someembodiments, the device is adapted to treat a sexually transmitteddisease. In some embodiments, the device is adapted to substantiallyprevent pregnancy. In some embodiments, the active agent comprises ahormone. In some embodiments, the pharmaceutical agent comprises ahormone. In some embodiments, the device is adapted to substantiallyprevent transmission of a sexually transmitted disease. In someembodiments, the device is adapted to treat an ailment of thereproductive system.

In some embodiments of the methods and/or devices provided herein, theintervention site is located in the urinary system of a subject. In someembodiments, the device is adapted to treat a disease of the urinarysystem. In some embodiments, the active agent comprises afluoroquinolone. In some embodiments, the pharmaceutical agent comprisesfluoroquinolone.

In some embodiments of the methods and/or devices provided herein, theintervention site is located at a tumor site. In some embodiments, thetumor site is where a tumor is located. In some embodiments, the tumorsite is where a tumor was located prior to removal and/or shrinkage ofthe tumor. In some embodiments, the active agent comprises mitomycin C.In some embodiments, the pharmaceutical agent comprises mitimycin C.

In some embodiments of the methods and/or devices provided herein, theintervention site is located in the ear. In some embodiments, theintervention site is located in the esophagus. In some embodiments, theactive agent comprises lidocaine. In some embodiments, thepharmaceutical agent comprises lidocaine.

In some embodiments of the methods and/or devices provided herein, theintervention site is located in the larynx. In some embodiments, theintervention site is a location of an injury. In some embodiments, theactive agent comprises CD34 antibodies.

In some embodiments of the methods and/or devices provided herein, theintervention site is an infection site. In some embodiments, theinfection site is a site wherein an infection may occur, and wherein theactive agent is capable of substantially preventing the infection. Insome embodiments, the infection site is a site wherein an infection hasoccurred, and wherein the active agent is capable of slowing spread ofthe infection. In some embodiments, the infection site is a site whereinan infection has occurred, and wherein the active agent is capable oftreating the infection. In some embodiments, the active agent comprisesan anti-infective agent. In some embodiments, the pharmaceutical agentcomprises an anti-infective agent. In some embodiments, theanti-infective agent comprises clindamycin.

In some embodiments of the methods and/or devices provided herein, theintervention site is a surgery site. In some embodiments, theintervention site is an ocular site.

In some embodiments of the methods and/or devices provided herein, thecoating is capable of promoting healing. In some embodiments, the activeagent comprises a growth factor. In some embodiments, the growth factorcomprises at least one of: an epidermal growth factor (EGF), atransforming growth factor-alpha (TGF-alpha), a hepatocyte growth factor(HGF), a vacscular endothelial growth factor (VEGF), a platelet derivedgrowth factor (PDGF), a fibroblast growth factor 1 (FGF-1), a fibroblastgrowth factor 2 (FGF-2), a transforming growth factor-beta (TGF-beta),and a keratinocyte growth factor (KGF). In some embodiments, the activeagent comprises a stem cell.

In some embodiments of the methods and/or devices provided herein, thecoating is capable of at least one of: retarding healing, delayinghealing, and preventing healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing theinflammatory phase of healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing theproliferative phase of healing. In some embodiments, the coating iscapable of at least one of: retarding, delaying, and preventing thematuration phase of healing. In some embodiments, the coating is capableof at least one of: retarding, delaying, and preventing the remodelingphase of healing. In some embodiments, the active agent comprises ananti-angiogenic agent.

In some embodiments of the methods and/or devices provided herein, thecoating is a sheath. In some embodiments, the sheath is plasticallydeformable. In some embodiments, at least a portion of the sheath iscapable of being left at the intervention site upon removal of thesubstrate from the intervention site. In some embodiments, the substrateis capable of mechanically deforming the sheath at the interventionsite.

In some embodiments of the methods and/or devices provided herein, thedevice comprises a retractable sheath. In some embodiments, the sheathis adapted to expose the coating to the intervention site uponretraction.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a bioadhesive. In some embodiments, the active agentcomprises a bioadhesive. In some embodiments, the coating closes avascular puncture. In some embodiments, the coating aids in closing avascular puncture.

In some embodiments of the methods and/or devices provided herein, thecoating substantially prevents adhesion of body tissue. In someembodiments, the coating promotes prevention of adhesion of body tissue.In some embodiments, the coating comprises hyaluronic acid, hyaluronate,salts, acids, conjugates, and/or derivatives thereof. In someembodiments, the active agent comprises hyaluronic acid, hyaluronate,salts, acids, conjugates, and/or derivatives thereof.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a plurality of layers deposited on said substrate,wherein at least one of the layers comprises the active agent. In someembodiments, at least one of the layers comprises a polymer. In someembodiments, the polymer is bioabsorbable. In some embodiments, theactive agent and the polymer are in the same layer, in separate layers,or form overlapping layers. In some embodiments, the coating comprises aplurality of layers deposited on said substrate, wherein at least one ofthe layers comprises the pharmaceutical agent. In some embodiments, thepharmaceutical agent and the polymer are in the same layer, in separatelayers, or form overlapping layers. In some embodiments, the pluralityof layers comprise five layers deposited as follows: a first polymerlayer, a first active agent layer, a second polymer layer, a secondactive agent layer and a third polymer layer. In some embodiments, theplurality of layers comprise five layers deposited as follows: a firstpolymer layer, a first pharmaceutical agent layer, a second polymerlayer, a second pharmaceutical agent layer and a third polymer layer. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active biological agentlayer, a second polymer layer, a second active biological agent layerand a third polymer layer.

In some embodiments of the methods and/or devices provided herein, thedevice provides the coating to the intervention site over an area ofdelivery greater than the outer surface contact area of the substrate.In some embodiments, the area of delivery is at least 110% greater thanthe outer surface contact area of the substrate. In some embodiments,the area of delivery is at least 110% to 200% greater than the outersurface contact area of the substrate. In some embodiments, the area ofdelivery is at least 200% greater than the outer surface contact area ofthe substrate.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andfreeing at least a portion of the coating from the substrate uponstimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, anddissociating at least a portion of the coating from the substrate uponstimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andtransferring at least a portion of the coating from the substrate to theintervention site upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating is at leastpartially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and freeing at least a portion of the coating fromthe substrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating is at leastpartially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and dissociating at least a portion of the coatingfrom the substrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating is at leastpartially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and transferring at least a portion of the coatingfrom the substrate to the intervention site upon stimulating the coatingwith a stimulation.

In some embodiments, the therapeutically desirable morphology comprisesa crystalline form of the pharmaceutical agent that is not amicrocapsule.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein said coating comprises anactive agent, and freeing greater than 35% of the coating from thesubstrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein said coating comprises anactive agent, and dissociating greater than 35% of the coating from thesubstrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein said coating comprises anactive agent, and transferring greater than 35% of the coating from thesubstrate to the intervention site upon stimulating the coating with astimulation.

In some embodiments, the single stimulation lasts at most 20 seconds. Insome embodiments, the device is adapted to free, dissociate, and/ortransfer substantially all of the coating upon the single stimulation ofthe coating. In some embodiments, substantially all of the coatingfrees, dissociates, and/or transfers from the substrate instantaneouslyupon stimulating the coating.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating comprises anactive agent, and wherein the coating is patterned, and freeing at leasta portion of the coating from the substrate upon stimulating the coatingwith a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating comprises anactive agent, and wherein the coating is patterned, and dissociatng atleast a portion of the coating from the substrate upon stimulating thecoating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating comprises anactive agent, and wherein the coating is patterned, and transferring atleast a portion of the coating from the substrate to the interventionsite upon stimulating the coating with a stimulation.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and transferring at least a portion of the coating fromthe substrate to an intervention site. In some embodiments, thetransferring the coating portion (i.e. the portion of the coating) fromthe substrate to the intervention site is upon stimulating the coatingwith a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and transferring at least a portion of the active agentfrom the substrate to an intervention site. In some embodiments, thetransferring the active agent portion (i.e. the portion of the activeagent) from the substrate to the intervention site is upon stimulatingthe coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and freeing at least a portion of the coating from thesubstrate at an intervention site. In some embodiments, the freeing thecoating portion (i.e. the portion of the coating) from the substrate isupon stimulating the coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and dissociating at least a portion of the coating fromthe substrate at an intervention site. In some embodiments, thedissociating the coating portion (i.e. the portion of the coating) fromthe substrate is upon stimulating the coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and depositing at least a portion of the coating at anintervention site. In some embodiments, the depositing the coatingportion (i.e. the portion of the coating) at the intervention site isupon stimulating the coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and tacking at least a portion of the coating to anintervention site. In some embodiments, the tacking the coating portion(i.e. the portion of the coating) to the intervention site is uponstimulating the coating with a stimulation.

In some embodiments of the methods and/or devices provided herein, thetransferring, freeing, dissociating, depositing, and/or tacking thecoating comprises extruding the coating from the substrate.

In some embodiments of the methods and/or devices provided herein,transferring at least a portion of the coating comprises transferring atleast about 10%, at least about 20%, at least about 30%, at least about50%, at least about 75%, at least about 85%, at least about 90%, atleast about 95%, and/or at least about 99% of the coating from thesubstrate. In some embodiments, stimulating decreases the contactbetween the coating and the substrate. In some embodiments, transferringtransfers less than about 1%, less than about 5%, less than about 10%.less than about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, and/or less than about 90% of thecoating absent stimulating at least one of the coating and thesubstrate.

In some embodiments of the methods and/or devices provided herein,transferring at least a portion of the active agent comprisestransferring at least about 10%, at least about 20%, at least about 30%,at least about 50%, at least about 75%, at least about 85%, at leastabout 90%, at least about 95%, and/or at least about 99% of the activeagent from the substrate. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,transferring transfers less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, less than about50%, less than about 70%, less than about 80%, and/or less than about90% of the active agent absent stimulating at least one of the coatingand the substrate.

In some embodiments of the methods and/or devices provided herein,freeing at least a portion of the coating comprises freeing at leastabout 10%, at least about 20%, at least about 30%, at least about 50%,at least about 75%, at least about 85%, at least about 90%, at leastabout 95%, and/or at least about 99% of the coating from the substrate.In some embodiments, stimulating decreases the contact between thecoating and the substrate. In some embodiments, freeing frees less thanabout 1%, less than about 5%, less than about 10%. less than about 15%,less than about 25%, less than about 50%, less than about 70%, less thanabout 80%, and/or less than about 90% of the coating absent stimulatingat least one of the coating and the substrate.

In some embodiments of the methods and/or devices provided herein,dissociating at least a portion of the coating comprises dissociating atleast about 10%, at least about 20%, at least about 30%, at least about50%, at least about 75%, at least about 85%, at least about 90%, atleast about 95%, and/or at least about 99% of the coating from thesubstrate. In some embodiments, stimulating decreases the contactbetween the coating and the substrate. In some embodiments, dissociatingdissociates less than about 1%, less than about 5%, less than about 10%.less than about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, and/or less than about 90% of thecoating absent stimulating at least one of the coating and thesubstrate.

In some embodiments of the methods and/or devices provided herein,depositing at least a portion of the coating comprises depositing atleast about 10%, at least about 20%, at least about 30%, at least about50%, at least about 75%, at least about 85%, at least about 90%, atleast about 95%, and/or at least about 99% of the coating at theintervention site. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,depositing deposits less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, less than about50%, less than about 70%, less than about 80%, and/or less than about90% of the coating absent stimulating at least one of the coating andthe substrate.

In some embodiments of the methods and/or devices provided herein,tacking at least a portion of the coating comprises tacking at leastabout 10%, at least about 20%, at least about 30%, at least about 50%,at least about 75%, at least about 85%, at least about 90%, at leastabout 95%, and/or at least about 99% of the coating to the interventionsite. In some embodiments, stimulating decreases the contact between thecoating and the substrate. In some embodiments, tacking tacks less thanabout 1%, less than about 5%, less than about 10%. less than about 15%,less than about 25%, less than about 50%, less than about 70%, less thanabout 80%, and/or less than about 90% of the coating absent stimulatingat least one of the coating and the substrate.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted totransfer from the substrate to an intervention site upon stimulating thecoating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without electricallycharging the substrate, wherein forming the coating results in at leasta portion of the coating being adapted to transfer from the substrate toan intervention site upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without creating anelectrical potential between the substrate and a coating apparatus usedin the at least one e-RESS, an e-SEDS, and an e-DPC process, whereinforming the coating results in at least a portion of the coating beingadapted to transfer from the substrate to an intervention site uponstimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to transferfrom the substrate to an intervention site upon stimulating the coatingwith a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent on ths substrate by a dippingand/or a spraying process, wherein forming the coating results ingreater than 35% of the coating being adapted to free from the substrateupon stimulating the coating with a single stimulation.

In some embodiments, the single stimulation lasts at most 20 seconds. Insome embodiments, substantially all of the coating is adapted totransfer from the substrate upon stimulating with a single stimulation.In some embodiments, substantially all of the coating frees from thesubstrate instantaneously upon stimulating the coating.

In some embodiments of the methods and/or devices provided herein,forming the coating results in the coating adhering to the substrateprior to the substrate reaching the intervention site.

Some embodiments of the methods and/or devices provided herein furthercomprise providing a release agent on said substrate. In someembodiments, providing the release agent step is performed prior to theforming the coating step. In some embodiments, the release agentcomprises at least one of: a biocompatible release agent, anon-biocompatible release agent, a powder, a lubricant, a surfacemodification of the substrate, a viscous fluid, a gel, the active agent,a second active agent, a physical characteristic of the substrate. Insome embodiments, the physical characteristic of the substrate comprisesat least one of: a patterned coating surface of the substrate, and aribbed surface of the substrate. In some embodiments, the release agentcomprises a property that is capable of changing at the interventionsite. In some embodiments, the property comprises a physical property.In some embodiments, the property comprises a chemical property. In someembodiments, the release agent is capable of changing a property when incontact with at least one of a biologic tissue and a biologic fluid. Insome embodiments, the release agent is capable of changing a propertywhen in contact with an aqueous liquid. In some embodiments, the coatingresults in a coating property that facilitates transfer of the coatingto the intervention site. In some embodiments, the coating propertycomprises a physical characteristic of the coating. In some embodiments,the physical characteristic comprises a pattern.

In some embodiments of the methods and/or devices provided herein,forming the coating facilitates transfer of the coating to theintervention site.

In some embodiments of the methods and/or devices provided herein,transferring, freeing, dissociating, depositing, and/or tacking stepcomprises softening the polymer by hydration, degradation or by acombination of hydration and degradation. In some embodiments, thetransferring, freeing, dissociating, depositing, and/or tacking stepcomprises softening the polymer by hydrolysis of the polymer.

In some embodiments of the methods and/or devices provided herein,providing the medical device comprises forming the coating out oflaminated layers that allow direct control of the transferring, freeing,depositing, tacking, and/or dissociating of the coating from thesubstrate. In some embodiments, the coating comprises laminated layersthat allow direct control of the transferring, freeing, depositing,tacking, and/or dissociating of the coating from the substrate, whereinat least one of the layers comprises the active agent. In someembodiments, the coating comprises laminated layers that allow directcontrol of the transferring, freeing, depositing, tacking, and/ordissociating of the coating from the substrate, wherein at least one ofthe layers comprises the pharmaceutical agent.

In some embodiments of the methods and/or devices provided herein, theproviding step comprises forming the coating by a solvent based coatingmethod. In some embodiments, the providing step comprises forming thecoating by a solvent plasma based method.

In some embodiments of the methods and/or devices provided herein,providing the device comprises depositing a plurality of layers on saidsubstrate to form the coating, wherein at least one of the layerscomprises the active agent. In some embodiments, at least one of thelayers comprises a polymer. In some embodiments, the polymer isbioabsorbable. In some embodiments, the active agent and the polymer arein the same layer, in separate layers, or form overlapping layers. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active agent layer, a secondpolymer layer, a second active agent layer and a third polymer layer.

In some embodiments of the methods and/or devices provided herein, thedevice further comprises a stent. In some embodiments, the substrate isnot the stent.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is explained in greater detail below. Thisdescription is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention. For example,features illustrated with respect to one embodiment may be incorporatedinto other embodiments, and features illustrated with respect to aparticular embodiment may be deleted from that embodiment. In addition,numerous variations and additions to the various embodiments suggestedherein will be apparent to those skilled in the art in light of theinstant disclosure, which do not depart from the instant invention.Hence, the following specification is intended to illustrate someparticular embodiments of the invention, and not to exhaustively specifyall permutations, combinations and variations thereof.

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

“Substrate” as used herein, refers to any surface upon which it isdesirable to deposit a coating. Biomedical implants are of particularinterest for the present invention; however the present invention is notintended to be restricted to this class of substrates. Those of skill inthe art will appreciate alternate substrates that could benefit from thecoating process described herein, such as pharmaceutical tablet cores,as part of an assay apparatus or as components in a diagnostic kit (e.g.a test strip). Examples of substrates that can be coated using themethods of the invention include surgery devices or medical devices,e.g., a catheter, a balloon, a cutting balloon, a wire guide, a cannula,tooling, an orthopedic device, a structural implant, stent, stent-graft,graft, vena cava filter, a heart valve, cerebrospinal fluid shunts,pacemaker electrodes, axius coronary shunts, endocardial leads, anartificial heart, and the like.

“Biomedical implant” as used herein refers to any implant for insertioninto the body of a human or animal subject, including but not limited tostents (e.g., coronary stents, vascular stents including peripheralstents and graft stents, urinary tract stents, urethral/prostaticstents, rectal stent, oesophageal stent, biliary stent, pancreaticstent), electrodes, catheters, leads, implantable pacemaker,cardioverter or defibrillator housings, joints, screws, rods, ophthalmicimplants, femoral pins, bone plates, grafts, anastomotic devices,perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysisgrafts, colostomy bag attachment devices, ear drainage tubes, leads forpace makers and implantable cardioverters and defibrillators, vertebraldisks, bone pins, suture anchors, hemostatic barriers, clamps, screws,plates, clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings (e.g., wound dressings), bonesubstitutes, intraluminal devices, vascular supports, etc.

The implants may be formed from any suitable material, including but notlimited to polymers (including stable or inert polymers, organicpolymers, organic-inorganic copolymers, inorganic polymers, andbiodegradable polymers), metals, metal alloys, inorganic materials suchas silicon, and composites thereof, including layered structures with acore of one material and one or more coatings of a different material.Substrates made of a conducting material facilitate electrostaticcapture. However, the invention contemplates the use of electrostaticcapture, as described herein, in conjunction with substrate having lowconductivity or which are non-conductive. To enhance electrostaticcapture when a non-conductive substrate is employed, the substrate isprocessed for example while maintaining a strong electrical field in thevicinity of the substrate. In some embodiments, however, noelectrostatic capture is employed in applying a coating to thesubstrate. In some embodiments of the methods and/or devices providedherein, the substrate is not charged in the coating process. In someembodiments of the methods and/or devices provided herein, an electricalpotential is not created between the substrate and the coatingapparatus.

Subjects into which biomedical implants of the invention may be appliedor inserted include both human subjects (including male and femalesubjects and infant, juvenile, adolescent, adult and geriatric subjects)as well as animal subjects (including but not limited to pig, rabbit,mouse, dog, cat, horse, monkey, etc.) for veterinary purposes and/ormedical research.

As used herein, a biological implant may include a medical device thatis not permanantly implanted. A biological implant in some embodimentsmay comprise a device which is used in a subject on a transient basis.For non-limiting example, the biomedical implant may be a balloon, whichis used transiently to dilate a lumen and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In some embodiments, the biological implant may betemporarily implanted for a limited time, such as during a portion of amedical procedure, or for only a limited time (some time less thanpermanantly implanted), or may be transiently implanted and/ormomentarily placed in the subject. In some embodiments, the biologicalimplant is not implanted at all, rather it is merely inserted into asubject during a medical procedure, and subsequently removed from thesubject prior to or at the time the medical procedure is completed. Insome embodiments, the biological implant is not permenantly implantedsince it completely resorbs into the subject (i.e. is completelyresorbed by the subject). In a preferred embodiment the biomedicalimplant is an expandable balloon that can be expanded within a lumen(naturally occuring or non-naturally occurring) having a coating thereonthat is freed (at least in part) from the balloon and left behind in thelumen when the balloon is removed from the lumen.

“Pharmaceutical agent” as used herein refers to any of a variety ofdrugs or pharmaceutical compounds that can be used as active agents toprevent or treat a disease (meaning any treatment of a disease in amammal, including preventing the disease, i.e. causing the clinicalsymptoms of the disease not to develop; inhibiting the disease, i.e.arresting the development of clinical symptoms; and/or relieving thedisease, i.e. causing the regression of clinical symptoms). It ispossible that the pharmaceutical agents of the invention may alsocomprise two or more drugs or pharmaceutical compounds. Pharmaceuticalagents include but are not limited to antirestenotic agents,antidiabetics, analgesics, antiinflammatory agents, antirheumatics,antihypotensive agents, antihypertensive agents, angiogenesis promoters,angiogenesis inhibitors, psychoactive drugs, tranquillizers,antiemetics, muscle relaxants, glucocorticoids, agents for treatingulcerative colitis or Crohn's disease, antiallergics, antibiotics,antiepileptics, anticoagulants, antimycotics, antifungals, antitussives,arteriosclerosis remedies, diuretics, proteins, peptides, enzymes,enzyme inhibitors, gout remedies, hormones and inhibitors thereof,cardiac glycosides, immunotherapeutic agents and cytokines, laxatives,lipid-lowering agents, migraine remedies, mineral products, otologicals,anti parkinson agents, thyroid therapeutic agents, spasmolytics,platelet aggregation inhibitors, vitamins, cytostatics and metastasisinhibitors, phytopharmaceuticals, chemotherapeutic agents and aminoacids. Examples of suitable active ingredients are acarbose, antigens,beta-receptor blockers, non-steroidal antiinflammatory drugs [NSAIDs],cardiac glycosides, acetylsalicylic acid, alfuzosim, virustatics,aclarubicin, acyclovir, cisplatin, actinomycin, alpha- andbeta-sympatomimetics, dmeprazole, allopurinol, alprostadil,prostaglandins, amantadine, ambroxol, amlodipine, methotrexate,S-aminosalicylic acid, amitriptyline, amoxicillin, anastrozole,atenolol, azathioprine, balsalazide, beclomethasone, betahistine,bezafibrate, bicalutamide, diazepam and diazepam derivatives,budesonide, bufexamac, buprenorphine, methadone, calcium salts,potassium salts, magnesium salts, candesartan, carbamazepine, captopril,cefalosporins, cetirizine, chenodeoxycholic acid, ursodeoxycholic acid,theophylline and theophylline derivatives, trypsins, cimetidine,clarithromycin, clavulanic acid, clindamycin, clobutinol, clonidine,cotrimoxazole, codeine, caffeine, vitamin D and derivatives of vitaminD, colestyramine, cromoglicic acid, coumarin and coumarin derivatives,cysteine, cytarabine, cyclophosphamide, ciclosporin, cyproterone,cytabarine, dapiprazole, desogestrel, desonide, dihydralazine,diltiazem, ergot alkaloids, dimenhydrinate, dimethyl sulphoxide,dimeticone, domperidone and domperidan derivatives, dopamine, doxazosin,doxorubizin, doxylamine, benzodiazepines, diclofenac, glycosideantibiotics, desipramine, econazole, ACE inhibitors, enalapril,ephedrine, epinephrine, epoetin and epoetin derivatives, morphinans,calcium antagonists, irinotecan, modafinil, orlistat, peptideantibiotics, phenytoin, riluzoles, risedronate, sildenafil, topiramate,macrolide antibiotics, oestrogen and oestrogen derivatives, progestogenand progestogen derivatives, testosterone and testosterone derivatives,androgen and androgen derivatives, ethenzamide, etofenamate, etofibrate,fenofibrate, etofylline, etoposide, famciclovir, famotidine, felodipine,fenofibrate, fentanyl, fenticonazole, gyrase inhibitors, fluconazole,fludarabine, fluarizine, fluorouracil, fluoxetine, flurbiprofen,ibuprofen, flutamide, fluvastatin, follitropin, formoterol, fosfomicin,furosemide, fusidic acid, gallopamil, ganciclovir, gemfibrozil,gentamicin, ginkgo, Saint John's wort, glibenclamide, urea derivativesas oral antidiabetics, glucagon, glucosamine and glucosaminederivatives, glutathione, glycerol and glycerol derivatives,hypothalamus hormones, goserelin, gyrase inhibitors, guanethidine,halofantrine, haloperidol, heparin and heparin derivatives, hyaluronicacid, hydralazine, hydrochlorothiazide and hydrochlorothiazidederivatives, salicylates, hydroxyzine, idarubicin, ifosfamide,imipramine, indometacin, indoramine, insulin, interferons, iodine andiodine derivatives, isoconazole, isoprenaline, glucitol and glucitolderivatives, itraconazole, ketoconazole, ketoprofen, ketotifen,lacidipine, lansoprazole, levodopa, levomethadone, thyroid hormones,lipoic acid and lipoic acid derivatives, lisinopril, lisuride,lofepramine, lomustine, loperamide, loratadine, maprotiline,mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine,meloxicam, mepindolol, meprobamate, meropenem, mesalazine, mesuximide,metamizole, metformin, methylphenidate, methylprednisolone, metixene,metoclopramide, metoprolol, metronidazole, mianserin, miconazole,minocycline, minoxidil, misoprostol, mitomycin, mizolastine, moexipril,morphine and morphine derivatives, evening primrose, nalbuphine,naloxone, tilidine, naproxen, narcotine, natamycin, neostigmine,nicergoline, nicethamide, nifedipine, niflumic acid, nimodipine,nimorazole, nimustine, nisoldipine, adrenaline and adrenalinederivatives, norfloxacin, novamine sulfone, noscapine, nystatin,ofloxacin, olanzapine, olsalazine, omeprazole, omoconazole, ondansetron,oxaceprol, oxacillin, oxiconazole, oxymetazoline, pantoprazole,paracetamol, paroxetine, penciclovir, oral penicillins, pentazocine,pentifylline, pentoxifylline, perphenazine, pethidine, plant extracts,phenazone, pheniramine, barbituric acid derivatives, phenylbutazone,pimozide, pindolol, piperazine, piracetam, pirenzepine, piribedil,piroxicam, pramipexole, pravastatin, prazosin, procaine, promazine,propiverine, propranolol, propyphenazone, prostaglandins, protionamide,proxyphylline, quetiapine, quinapril, quinaprilat, ramipril, ranitidine,reproterol, reserpine, ribavirin, rifampicin, risperidone, ritonavir,ropinirole, roxatidine, roxithromycin, ruscogenin, rutoside and rutosidederivatives, sabadilla, salbutamol, salmeterol, scopolamine, selegiline,sertaconazole, sertindole, sertralion, silicates, simvastatin,sitosterol, sotalol, spaglumic acid, sparfloxacin, spectinomycin,spiramycin, spirapril, spironolactone, stavudine, streptomycin,sucralfate, sufentanil, sulbactam, sulphonamides, sulfasalazine,sulpiride, sultamicillin, sultiam, sumatriptan, suxamethonium chloride,tacrine, tacrolimus, taliolol, tamoxifen, taurolidine, tazarotene,temazepam, teniposide, tenoxicam, terazosin, terbinafine, terbutaline,terfenadine, terlipressin, tertatolol, tetracyclins, teryzoline,theobromine, theophylline, butizine, thiamazole, phenothiazines,thiotepa, tiagabine, tiapride, propionic acid derivatives, ticlopidine,timolol, tinidazole, tioconazole, tioguanine, tioxolone, tiropramide,tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate, tolperisone,topotecan, torasemide, antioestrogens, tramadol, tramazoline,trandolapril, tranylcypromine, trapidil, trazodone, triamcinolone andtriamcinolone derivatives, triamterene, trifluperidol, trifluridine,trimethoprim, trimipramine, tripelennamine, triprolidine, trifosfamide,tromantadine, trometamol, tropalpin, troxerutine, tulobuterol, tyramine,tyrothricin, urapidil, ursodeoxycholic acid, chenodeoxycholic acid,valaciclovir, valproic acid, vancomycin, vecuronium chloride, Viagra,venlafaxine, verapamil, vidarabine, vigabatrin, viloazine, vinblastine,vincamine, vincristine, vindesine, vinorelbine, vinpocetine, viquidil,warfarin, xantinol nicotinate, xipamide, zafirlukast, zalcitabine,zidovudine, zolmitriptan, zolpidem, zoplicone, zotipine, clotrimazole,amphotericin B, caspofungin, or voriconazole, resveratrol, PARP-1inhibitors (including imidazoquinolinone, imidazpyridine, andisoquinolindione, tissue plasminogen activator (tPA), melagatran,lanoteplase, reteplase, staphylokinase, streptokinase, tenecteplase,urokinase, and the like. See, e.g., U.S. Pat. No. 6,897,205; see alsoU.S. Pat. No. 6,838,528; U.S. Pat. No. 6,497,729.

Examples of pharmaceutical agents employed in conjunction with theinvention include, rapamycin, 40-O-(2-Hydroxyethyl)rapamycin(everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 4O—O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin4O—O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,4O—O-(2-Acetoxy)ethyl-rapamycin 4O—O-(2-Nicotinoyloxy)ethyl-rapamycin,4O—O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin4O—O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,4O—O-(2-Aminoethyl)-rapamycin, 4O—O-(2-Acetaminoethyl)-rapamycin4O—O-(2-Nicotinamidoethyl)-rapamycin,4O—O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,4O—O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

In some embodiments, a pharmaceutical agent is at least one of:Acarbose, acetylsalicylic acid, acyclovir, allopurinol, alprostadil,prostaglandins, amantadine, ambroxol, amlodipine, S-aminosalicylic acid,amitriptyline, atenolol, azathioprine, balsalazide, beclomethasone,betahistine, bezafibrate, diazepam and diazepam derivatives, budesonide,bufexamac, buprenorphine, methadone, calcium salts, potassium salts,magnesium salts, candesartan, carbamazepine, captopril, cetirizine,chenodeoxycholic acid, theophylline and theophylline derivatives,trypsins, cimetidine, clobutinol, clonidine, cotrimoxazole, codeine,caffeine, vitamin D and derivatives of vitamin D, colestyramine,cromoglicic acid, coumarin and coumarin derivatives, cysteine,ciclosporin, cyproterone, cytabarine, dapiprazole, desogestrel,desonide, dihydralazine, diltiazem, ergot alkaloids, dimenhydrinate,dimethyl sulphoxide, dimeticone, domperidone and domperidan derivatives,dopamine, doxazosin, doxylamine, benzodiazepines, diclofenac,desipramine, econazole, ACE inhibitors, enalapril, ephedrine,epinephrine, epoetin and epoetin derivatives, morphinans, calciumantagonists, modafinil, orlistat, peptide antibiotics, phenytoin,riluzoles, risedronate, sildenafil, topiramate, estrogen, progestogenand progestogen derivatives, testosterone derivatives, androgen andandrogen derivatives, ethenzamide, etofenamate, etofibrate, fenofibrate,etofylline, famciclovir, famotidine, felodipine, fentanyl,fenticonazole, gyrase inhibitors, fluconazole, fluarizine, fluoxetine,flurbiprofen, ibuprofen, fluvastatin, follitropin, formoterol,fosfomicin, furosemide, fusidic acid, gallopamil, ganciclovir,gemfibrozil, ginkgo, Saint John's wort, glibenclamide, urea derivativesas oral antidiabetics, glucagon, glucosamine and glucosaminederivatives, glutathione, glycerol and glycerol derivatives,hypothalamus hormones, guanethidine, halofantrine, haloperidol, heparin(and derivatives), hyaluronic acid, hydralazine, hydrochlorothiazide(and derivatives), salicylates, hydroxyzine, imipramine, indometacin,indoramine, insulin, iodine and iodine derivatives, isoconazole,isoprenaline, glucitol and glucitol derivatives, itraconazole,ketoprofen, ketotifen, lacidipine, lansoprazole, levodopa,levomethadone, thyroid hormones, lipoic acid (and derivatives),lisinopril, lisuride, lofepramine, loperamide, loratadine, maprotiline,mebendazole, mebeverine, meclozine, mefenamic acid, mefloquine,meloxicam, mepindolol, meprobamate, mesalazine, mesuximide, metamizole,metformin, methylphenidate, metixene, metoprolol, metronidazole,mianserin, miconazole, minoxidil, misoprostol, mizolastine, moexipril,morphine and morphine derivatives, evening primrose, nalbuphine,naloxone, tilidine, naproxen, narcotine, natamycin, neostigmine,nicergoline, nicethamide, nifedipine, niflumic acid, nimodipine,nimorazole, nimustine, nisoldipine, adrenaline and adrenalinederivatives, novamine sulfone, noscapine, nystatin, olanzapine,olsalazine, omeprazole, omoconazole, oxaceprol, oxiconazole,oxymetazoline, pantoprazole, paracetamol (acetaminophen), paroxetine,penciclovir, pentazocine, pentifylline, pentoxifylline, perphenazine,pethidine, plant extracts, phenazone, pheniramine, barbituric acidderivatives, phenylbutazone, pimozide, pindolol, piperazine, piracetam,pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin,procaine, promazine, propiverine, propranolol, propyphenazone,protionamide, proxyphylline, quetiapine, quinapril, quinaprilat,ramipril, ranitidine, reproterol, reserpine, ribavirin, risperidone,ritonavir, ropinirole, roxatidine, ruscogenin, rutoside (andderivatives), sabadilla, salbutamol, salmeterol, scopolamine,selegiline, sertaconazole, sertindole, sertralion, silicates,simvastatin, sitosterol, sotalol, spaglumic acid, spirapril,spironolactone, stavudine, streptomycin, sucralfate, sufentanil,sulfasalazine, sulpiride, sultiam, sumatriptan, suxamethonium chloride,tacrine, tacrolimus, taliolol, taurolidine, temazepam, tenoxicam,terazosin, terbinafine, terbutaline, terfenadine, terlipressin,tertatolol, teryzoline, theobromine, butizine, thiamazole,phenothiazines, tiagabine, tiapride, propionic acid derivatives,ticlopidine, timolol, tinidazole, tioconazole, tioguanine, tioxolone,tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate,tolperisone, topotecan, torasemide, tramadol, tramazoline, trandolapril,tranylcypromine, trapidil, trazodone, triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimipramine, tripelennamine,triprolidine, trifosfamide, tromantadine, trometamol, tropalpin,troxerutine, tulobuterol, tyramine, tyrothricin, urapidil, valaciclovir,valproic acid, vancomycin, vecuronium chloride, Viagra, venlafaxine,verapamil, vidarabine, vigabatrin, viloazine, vincamine, vinpocetine,viquidil, warfarin, xantinol nicotinate, xipamide, zafirlukast,zalcitabine, zidovudine, zolmitriptan, zolpidem, zoplicone, zotipine,amphotericin B, caspofungin, voriconazole, resveratrol, PARP-1inhibitors (including imidazoquinolinone, imidazpyridine, andisoquinolindione, tissue plasminogen activator (tPA), melagatran,lanoteplase, reteplase, staphylokinase, streptokinase, tenecteplase,urokinase, 40-O-(2-Hydroxyethyl)rapamycin (everolimus),40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 4O—O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin4O—O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,4O—O-(2-Acetoxy)ethyl-rapamycin 4O—O-(2-Nicotinoyloxy)ethyl-rapamycin,4O—O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin4O—O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,4O—O-(2-Aminoethyl)-rapamycin, 4O—O-(2-Acetaminoethyl)-rapamycin4O—O-(2-Nicotinamidoethyl)-rapamycin,4O—O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,4O—O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus), abciximab (ReoPro), eptifibatide, tirofiban, prasugrel,clopidogrel, dipyridamole, cilostazol, VEGF, heparan sulfate,chondroitin sulfate, elongated “RGD” peptide binding domain, CD34antibodies, cerivastatin, etorvastatin, losartan, valartan,erythropoietin, rosiglitazone, pioglitazone, mutant protein Apo A1Milano, adiponectin, (NOS) gene therapy, glucagon-like peptide 1,atorvastatin, and atrial natriuretic peptide (ANP), lidocaine,tetracaine, dibucaine, hyssop, ginger, turmeric, Arnica montana,helenalin, cannabichromene, rofecoxib, and hyaluronidase.

The pharmaceutical agents may, if desired, also be used in the form oftheir pharmaceutically acceptable salts or derivatives (meaning saltswhich retain the biological effectiveness and properties of thecompounds of this invention and which are not biologically or otherwiseundesirable), and in the case of chiral active ingredients it ispossible to employ both optically active isomers and racemates ormixtures of diastereoisomers. As well, the pharmaceutical agent mayinclude a prodrug, a hydrate, an ester, a derivative or analogs of acompound or molecule.

The pharmaceutical agent may be an antibiotic agent, as describedherein.

The pharmaceutical agent may be a chemotherapeutic agent, as describedherein.

The phamaceutical agent may be an anti-thrombotic agent, as describedherein.

The phamaceutical agent may be a statin, as described herein.

The phamaceutical agent may be an angiogenisis promoter, as describedherein.

The phamaceutical agent may be a local anesthetic, as described herein.

The phamaceutical agent may be an anti-inflammatory agent, as describedherein.

A “pharmaceutically acceptable salt” may be prepared for anypharmaceutical agent having a functionality capable of forming a salt,for example an acid or base functionality. Pharmaceutically acceptablesalts may be derived from organic or inorganic acids and bases. The term“pharmaceutically-acceptable salts” in these instances refers to therelatively non-toxic, inorganic and organic base addition salts of thepharmaceutical agents.

“Prodrugs” are derivative compounds derivatized by the addition of agroup that endows greater solubility to the compound desired to bedelivered. Once in the body, the prodrug is typically acted upon by anenzyme, e.g., an esterase, amidase, or phosphatase, to generate theactive compound.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.There are many chemotherapeutic agents available in commercial use, inclinical evaluation and in pre-clinical development that are useful inthe devices and methods of the present invention for treatment ofcancers.

In some embodiments, a chemotherapeutic agent comprises at least one ofan angiostatin, DNA topoisomerase, endostatin, genistein, ornithinedecarboxylase inhibitors, chlormethine, melphalan, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine(BCNU), streptozocin, 6-mercaptopurine, 6-thioguanine, Deoxyco-formycin,IFN-α, 17α-ethinylestradiol, diethylstilbestrol, testosterone,prednisone, fluoxymesterone, dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyl-testosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, estramustine,medroxyprogesteroneacetate, flutamide, zoladex, mitotane,hexamethylmelamine, indolyl-3-glyoxylic acid derivatives, (e.g.,indibulin), doxorubicin and idarubicin, plicamycin (mithramycin) andmitomycin, mechlorethamine, cyclophosphamide analogs,trazenes-dacarbazinine (DTIC), pentostatin and 2-chlorodeoxyadenosine,letrozole, camptothecin (and derivatives), navelbine, erlotinib,capecitabine, acivicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, ambomycin, ametantrone acetate, anthramycin, asperlin,azacitidine, azetepa, azotomycin, batimastat, benzodepa, bisnafide,bisnafide dimesylate, bizelesin, bropirimine, cactinomycin, calusterone,carbetimer, carubicin hydrochloride, carzelesin, cedefingol, celecoxib(COX-2 inhibitor), cirolemycin, crisnatol mesylate, decitabine,dexormaplatin, dezaguanine mesylate, diaziquone, duazomycin, edatrexate,eflomithine, elsamitrucin, enloplatin, enpromate, epipropidine,erbulozole, etanidazole, etoprine, flurocitabine, fosquidone,lometrexol, losoxantrone hydrochloride, masoprocol, maytansine,megestrol acetate, melengestrol acetate, metoprine, meturedepa,mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitosper,mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran,pegaspargase, peliomycin, pentamustine, perfosfamide, piposulfan,plomestane, porfimer sodium, porfiromycin, puromycin, pyrazofurin,riboprine, safingol, simtrazene, sparfosate sodium, spiromustine,spiroplatin, streptonigrin, sulofenur, tecogalan sodium, taxotere,tegafur, teloxantrone hydrochloride, temoporfin, thiamiprine,tirapazamine, trestolone acetate, triciribine phosphate, trimetrexateglucuronate, tubulozole hydrochloride, uracil mustard, uredepa,verteporfin, vinepidine sulfate, vinglycinate sulfate, vinleurosinesulfate, vinorelbine tartrate, vinrosidine sulfate, zeniplatin,zinostatin, 20-epi-1,25 dihydroxyvitamin D3, 5-ethynyluracil,acylfulvene, adecypenol, ALL-TK antagonists, ambamustine, amidox,amifostine, aminolevulinic acid, amrubicin, anagrelide, andrographolide,antagonist D, antagonist G, antarelix, anti-dorsalizing morphogeneticprotein-1, antiandrogen, antiestrogen, estrogen agonist, apurinic acid,ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane,atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron,azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR/ABLantagonists, benzochlorins, benzoylstaurosporine, beta lactamderivatives, beta-alethine, betaclamycin B, betulinic acid, bFGFinhibitor, bisaziridinylspermine, bistratene A, breflate, buthioninesulfoximine, calcipotriol, calphostin C, carboxamide-amino-triazole,carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived inhibitor,casein kinase inhibitors (ICOS), castanospermine, cecropin B,cetrorelix, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin,clomifene analogues, clotrimazole, collismycin A, collismycin B,combretastatin A4, combretastatin analogue, conagenin, crambescidin 816,cryptophycin 8, cryptophycin A derivatives, curacin A,cyclopentanthraquinones, cycloplatam, cypemycin, cytolytic factor,cytostatin, dacliximab, dehydrodidemnin B, dexamethasone, dexifosfamide,dexrazoxane, dexverapamil, didemnin B, didox, diethylnorspermine,dihydro-5-azacytidine, dihydrotaxol, 9-, dioxamycin, docosanol,dolasetron, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine,edrecolomab, elemene, emitefur, estramustine analogue, filgrastim,flavopiridol, flezelastine, fluasterone, fluorodaunorunicinhydrochloride, forfenimex, gadolinium texaphyrin, galocitabine,gelatinase inhibitors, glutathione inhibitors, hepsulfam, heregulin,hexamethylene bisacetamide, hypericin, ibandronic acid, idramantone,ilomastat, imatinib (e.g., Gleevec), imiquimod, immunostimulantpeptides, insulin-like growth factor-1 receptor inhibitor, interferonagonists, interferons, interleukins, iobenguane, iododoxorubicin,ipomeanol, 4-, iroplact, irsogladine, isobengazole, isohomohalicondrinB, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate,leinamycin, lenograstim, lentinan sulfate, leptolstatin, leukemiainhibiting factor, leukocyte alpha interferon,leuprolide+estrogen+progesterone, linear polyamine analogue, lipophilicdisaccharide peptide, lipophilic platinum compounds, lissoclinamide 7,lobaplatin, lombricine, loxoribine, lurtotecan, lutetium texaphyrin,lysofylline, lytic peptides, maitansine, mannostatin A, marimastat,maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors,meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone,miltefosine, mirimostim, mitoguazone, mitotoxin fibroblast growthfactor-saporin, mofarotene, molgramostim, Erbitux, human chorionicgonadotrophin, monophosphoryl lipid A+myobacterium cell wall sk, mustardanticancer agent, mycaperoxide B, mycobacterial cell wall extract,myriaporone, N-acetyldinaline, N-substituted benzamides, nagrestip,naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin,nemorubicin, neridronic acid, nisamycin, nitric oxide modulators,nitroxide antioxidant, nitrullyn, oblimersen (Genasense),O⁶-benzylguanine, okicenone, onapristone, ondansetron, oracin, oralcytokine inducer, paclitaxel analogues and derivatives, palauamine,palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifene, parabactin,peldesine, pentosan polysulfate sodium, pentrozole, perflubron, perillylalcohol, phenazinomycin, phenylacetate, phosphatase inhibitors,picibanil, pilocarpine hydrochloride, placetin A, placetin B,plasminogen activator inhibitor, platinum complex, platinum compounds,platinum-triamine complex, propyl bis-acridone, prostaglandin J2,proteasome inhibitors, protein A-based immune modulator, protein kinaseC inhibitors, microalgal, pyrazoloacridine, pyridoxylated hemoglobinpolyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, rasfarnesyl protein transferase inhibitors, ras-GAP inhibitor, retelliptinedemethylated, rhenium Re 186 etidronate, ribozymes, RII retinamide,rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saintopin,SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetics, senescence derivedinhibitor 1, signal transduction inhibitors, sizofiran, sobuzoxane,sodium borocaptate, solverol, somatomedin binding protein, sonermin,sparfosic acid, spicamycin D, splenopentin, spongistatin 1, squalamine,stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactiveintestinal peptide antagonist, suradista, suramin, swainsonine,tallimustine, tazarotene, tellurapyrylium, telomerase inhibitors,tetrachlorodecaoxide, tetrazomine, thiocoraline, thrombopoietin,thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist,thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin,titanocene bichloride, topsentin, translation inhibitors, tretinoin,triacetyluridine, tropisetron, turosteride, ubenimex, urogenitalsinus-derived growth inhibitory factor, variolin B, velaresol, veramine,verdins, vinxaltine, vitaxin, zanoterone, zilascorb, zinostatinstimalamer, acanthifolic acid, aminothiadiazole, anastrozole,bicalutamide, brequinar sodium, capecitabine, carmofur, Ciba-GeigyCGP-30694, cladribine, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, cytarabine ocfosfate, Lilly DATHF,Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox,Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015,fazarabine, floxuridine, fludarabine, fludarabine phosphate,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152,5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011, LillyLY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine,nolvadex, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi ChemicalPL-AC, stearate, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF,trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinaseinhibitors, Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamideanalogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207,bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine(BiCNU), Chinoin-139, Chinoin-153, chlorambucil, cisplatin,cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate,dacarbazine, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Chugai DWA-2114R, ITI E09,elmustine, Erbamont FCE-24517, estramustine phosphate sodium, etoposidephosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam,ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol,mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, thiotepa, Yakult Honsha SN-22,spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol, Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative,Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins,anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B,Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b,Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitomycinanalogues, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon KayakuNK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine,oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin,pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin,sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow BrandSN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SSPharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B,Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine,tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405,Yoshitomi Y-25024, zorubicin, 5-fluorouracil (5-FU), the peroxidateoxidation product of inosine, adenosine, or cytidine with methanol orethanol, cytosine arabinoside (also referred to as Cytarabin, araC, andCytosar), 5-Azacytidine, 2-Fluoroadenosine-5′-phosphate (Fludara, alsoreferred to as FaraA), 2-Chlorodeoxyadenosine, Abarelix, Abbott A-84861,Abiraterone acetate, Aminoglutethimide, Asta Medica AN-207, Antide,Chugai AG-041R, Avorelin, aseranox, Sensus B2036-PEG, buserelin, BTGCB-7598, BTG CB-7630, Casodex, cetrolix, clastroban, clodronatedisodium, Cosudex, Rotta Research CR-1505, cytadren, crinone,deslorelin, droloxifene, dutasteride, Elimina, Laval University EM-800,Laval University EM-652, epitiostanol, epristeride, Mediolanum EP-23904,EntreMed 2-ME, exemestane, fadrozole, finasteride, formestane, Pharmacia& Upjohn FCE-24304, ganirelix, goserelin, Shire gonadorelin agonist,Glaxo Wellcome GW-5638, Hoechst Marion Roussel Hoe-766, NCI hCG,idoxifene, isocordoin, Zeneca ICI-182780, Zeneca ICI-118630, TulaneUniversity J015X, Schering Ag J96, ketanserin, lanreotide, MilkhausLDI-200, letrozol, leuprolide, leuprorelin, liarozole, lisuride hydrogenmaleate, loxiglumide, mepitiostane, Ligand Pharmaceuticals LG-1127,LG-1447, LG-2293, LG-2527, LG-2716, Bone Care International LR-103,Lilly LY-326315, Lilly LY-353381-HCl, Lilly LY-326391, Lilly LY-353381,Lilly LY-357489, miproxifene phosphate, Orion Pharma MPV-2213ad, TulaneUniversity MZ-4-71, nafarelin, nilutamide, Snow Brand NKS01, Azko NobelORG-31710, Azko Nobel ORG-31806, orimeten, orimetene, orimetine,ormeloxifene, osaterone, Smithkline Beecham SKB-105657, Tokyo UniversityOSW-1, Peptech PTL-03001, Pharmacia & Upjohn PNU-156765, quinagolide,ramorelix, Raloxifene, statin, sandostatin LAR, Shionogi S-10364,Novartis SMT-487, somavert, somatostatin, tamoxifen, tamoxifenmethiodide, teverelix, toremifene, triptorelin, TT-232, vapreotide,vorozole, Yamanouchi YM-116, Yamanouchi YM-511, Yamanouchi YM-55208,Yamanouchi YM-53789, Schering AG ZK-1911703, Schering AG ZK-230211, andZeneca ZD-182780, alpha-carotene, alpha-difluoromethyl-arginine,acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10,antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplastonAS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol,baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015,bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide,Wellcome BW-502, Wellcome BW-773, calcium carbonate, Calcet, Calci-Chew,Calci-Mix, Roxane calcium carbonate tablets, caracemide, carmethizolehydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053,Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937,Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone,ICN compound 1259, ICN compound 4711, Contracan, Cell Pathways CP-461,Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine,cytocytin, Merz D-609, DABIS maleate, datelliptinium, DFMO, didemnin-B,dihaematoporphyrin ether, dihydrolenperone dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel,Encore Pharmaceuticals E7869, elliprabin, elliptinium acetate, TsumuraEPMTC, ergotamine, etoposide, etretinate, Eulexin, Cell PathwaysExisulind (sulindac sulphone or CP-246), fenretinide, Florical, FujisawaFR-57704, gallium nitrate, gemcitabine, genkwadaphnin, Gerimed, ChugaiGLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, GreenCross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine,irinotecan, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477,ketoconazole, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110,American Cyanamid L-623, leucovorin, levamisole, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP,marycin, Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone,merocyanine derivatives, methylanilinoacridine, Molecular GeneticsMGI-136, minactivin, mitonafide, mitoquidone, Monocal, mopidamol,motretinide, Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids,Nilandron, Nisshin Flour Milling N-021, N-acylated-dehydroalanines,nafazatrom, Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative,Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCINSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, retinoids, R-flurbiprofen(Encore Pharmaceuticals), Sandostatin, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, Scherring-Plough SC-57050, Scherring-PloughSC-57068, selenium (selenite and selenomethionine), SmithKlineSK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol,spirocyclopropane derivatives, spirogermanium, Unimed, SS PharmaceuticalSS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071,Sugen SU-101, Sugen SU-5416, Sugen SU-6668, sulindac, sulindac sulfone,superoxide dismutase, Toyama T-506, Toyama T-680, taxol, TeijinTEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol,Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028,ukrain, Eastman Kodak USB-006, vinblastine, vinblastine sulfate,vincristine, vincristine sulfate, vindesine, vindesine sulfate,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides,Yamanouchi YM-534, Zileuton, ursodeoxycholic acid, Zanosar.

Chemotherapeutic agents and dosing recommendations for treating specificdiseases, are described at length in the literature, e.g., in U.S. Pat.No. 6,858,598, “Method of Using a Matrix Metalloproteinase Inhibitor andOne or More Antineoplastic Agents as a Combination Therapy in theTreatment of Neoplasia,” and U.S. Pat. No. 6,916,800, “CombinationTherapy Including a Matrix Metalloproteinase Inhibitor and anAntineoplastic Agent,” both incorporated herein by reference in theirentirety.

Methods for the safe and effective administration of chemotherapeuticagents are known to those skilled in the art. In addition, theiradministration is described in the standard literature. For example, theadministration of many chemotherapeutic agents is described in the“Physicians' Desk Reference” (PDR), e.g., 1996 edition (MedicalEconomics Company, Montvale, N.J. 07645-1742, USA), incorporated hereinby reference.

Combinations of two or more agents can be used in the devices andmethods of the invention. Guidance for selecting drug combinations forgiven indications is provided in the published literature, e.g., in the“Drug Information Handbook for Oncology: A Complete Guide to CombinationChemotherapy Regimens” (edited by Dominic A. Solimando, Jr., MA BCOP;published by Lexi-Comp, Hudson, Ohio, 2007. ISBN 978-1-59195-175-9), aswell as in U.S. Pat. No. 6,858,598. Specific combinations ofchemotherapeutic agents having enhanced activity relative to theindividual agents, are described in, e.g., WO 02/40702, “Methods for theTreatment of Cancer and Other Diseases and Methods of Developing theSame,” incorporated herein by reference in its entirety. WO 02/40702reports enhanced activity when treating cancer using a combination of aplatin-based compound (e.g., cisplatin, oxoplatin), a folate inhibitor(e.g., MTA, ALIMTA, LY231514), and deoxycytidine or an analogue thereof(e.g., cytarabin, gemcitabine).

Chemotherapeutic agents can be classified into various groups, e.g., ACEinhibitors, alkylating agents, angiogenesis inhibitors,anthracyclines/DNA intercalators, anti-cancer antibiotics orantibiotic-type agents, antimetabolites, antimetastatic compounds,asparaginases, bisphosphonates, cGMP phosphodiesterase inhibitors,cyclooxygenase-2 inhibitors DHA derivatives, epipodophylotoxins,hormonal anticancer agents, hydrophilic bile acids (URSO),immunomodulators or immunological agents, integrin antagonists,interferon antagonists or agents, MMP inhibitors, monoclonal antibodies,nitrosoureas, NSAIDs, ornithine decarboxylase inhibitors, radio/chemosensitizers/protectors, retinoids, selective inhibitors of proliferationand migration of endothelial cells, selenium, stromelysin inhibitors,taxanes, vaccines, and vinca alkaloids.

Alternatively, chemotherapeutic agents can be classified by target,e.g., agents can be selected from a tubulin binding agent, a kinaseinhibitor (e.g., a receptor tyrosine kinase inhibitor), ananti-metabolic agent, a DNA synthesis inhibitor, and a DNA damagingagent.

Other classes into which chemotherapeutic agents can be divided include:alkylating agents, antimetabolites, natural products and theirderivatives, hormones and steroids (including synthetic analogs), andsynthetics. Examples of compounds within these classes are given herein.

Alkylating agents (e.g., nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes) include Uracil mustard,Chlormethine, Cyclophosphamide (Cytoxan), Ifosfamide, Melphalan,Chlorambucil, Pipobroman, Triethylene-melamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

Antimetabolites (e.g., folic acid antagonists, pyrimidine analogs,purine analogs and adenosine deaminase inhibitors) include Methotrexate,5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

Natural products and their derivatives (e.g., vinca alkaloids, antitumorantibiotics, enzymes, lymphokines and epipodophyllotoxins) includeVinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel(paclitaxel is commercially available as Taxol), Mithramycin,Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especiallyIFN-α), Etoposide, and Teniposide.

Hormones and steroids (e.g., synthetic analogs) include17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, Zoladex.

Synthetics (e.g., inorganic complexes such as platinum coordinationcomplexes) include Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, andHexamethylmelamine.

Chemotherapeutic agents can also be classified by chemical family, forexample, therapeutic agents selected from vinca alkaloids (e.g.,vinblastine, vincristine, and vinorelbine), taxanes (e.g., paclitaxeland docetaxel), indolyl-3-glyoxylic acid derivatives, (e.g., indibulin),epidipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g.,dactinomycin or actinomycin D, daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (e.g., mechlorethamine, ifosphamide, cyclophosphamide andanalogs, melphalan, chlorambucil), ethylenimines and methylmelamines(e.g., hexamethylmelamine and thiotepa), alkyl sulfonates (busulfan),nitrosoureas (e.g., carmustine (BCNU) and analogs, streptozocin),trazenes-dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (e.g., methotrexate),pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine),purine analogs and related inhibitors (e.g., mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine); aromataseinhibitors (e.g., anastrozole, exemestane, and letrozole); and platinumcoordination complexes (e.g., cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (e.g., estrogen) andhormone agonists such as leutinizing hormone releasing hormone (LHRH)agonists (e.g., goserelin, leuprolide and triptorelin).

Antineoplastic agents are often placed into categories, includingantimetabolite agents, alkylating agents, antibiotic-type agents,hormonal anticancer agents, immunological agents, interferon-typeagents, and a category of miscellaneous antineoplastic agents. Someantineoplastic agents operate through multiple or unknown mechanisms andcan thus be classified into more than one category.

A first family of antineoplastic agents which may be used in combinationwith the present invention consists of antimetabolite-typeantineoplastic agents. Antimetabolites are typically reversible orirreversible enzyme inhibitors, or compounds that otherwise interferewith the replication, translation or transcription of nucleic acids.Suitable antimetabolite antineoplastic agents that may be used in thepresent invention include, but are not limited to acanthifolic acid,aminothiadiazole, anastrozole, bicalutamide, brequinar sodium,capecitabine, carmofur, Ciba-Geigy CGP-30694, cladribine, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugates,cytarabine ocfosfate, Lilly DATHF, Merrel Dow DDFC, dezaguanine,dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine,Wellcome EHNA, Merck & Co. EX-015, fazarabine, finasteride, floxuridine,fludarabine, fludarabine phosphate, N-(2′-furanidyl)-5-fluorouracil,Daiichi Seiyaku FO-152, fluorouracil (5-FU), 5-FU-fibrinogen, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, nafarelin, norspermidine, nolvadex, NCINSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi ChemicalPL-AC, stearate; Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF,trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinaseinhibitors, Taiho UFT, toremifene, and uricytin.

Antimetabolite agents that may be used in the present invention include,but are not limited to, those identified in Table No. 5 of U.S. Pat. No.6,858,598, incorporated herein by reference.

A second family of antineoplastic agents which may be used incombination with the present invention consists of alkylating-typeantineoplastic agents. The alkylating agents are believed to act byalkylating and cross-linking guanine and possibly other bases in DNA,arresting cell division. Typical alkylating agents include nitrogenmustards, ethyleneimine compounds, alkyl sulfates, cisplatin, andvarious nitrosoureas. A disadvantage with these compounds is that theynot only attack malignant cells, but also other cells which arenaturally dividing, such as those of bone marrow, skin,gastro-intestinal mucosa, and fetal tissue. Suitable alkylating-typeantineoplastic agents that may be used in the present invention include,but are not limited to, Shionogi 254-S, aldo-phosphamide analogues,altretamine, anaxirone, Boehringer Mannheim BBR-2207, bestrabucil,budotitane, Wakunaga CA-102, carboplatin, carmustine (BiCNU),Chinoin-139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide,American Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarbazine,Degussa D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinumcytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09,elmustine, Erbamont FCE-24517, estramustine phosphate sodium, etoposidephosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam,ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol,mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, thiotepa, Yakult Honsha SN-22,spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol.

Preferred alkylating agents that may be used in the present inventioninclude, but are not limited to, those identified in those identified inTable No. 6 of U.S. Pat. No. 6,858,598, incorporated herein byreference.

A third family of antineoplastic agents which may be used in combinationwith the present invention consists of antibiotic-type antineoplasticagents. Suitable antibiotic-type antineoplastic agents that may be usedin the present invention include, but are not limited to Taiho 4181-A,aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, NipponSoda anisomycins, anthracycline, azino-mycin-A, bisucaberin,Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551,Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-MyersBMY-28438, bleomycin sulfate, bryostatin-1, Taiho C-1027, calichemycin,chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, KyowaHakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa HakkoDC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin,doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin,esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954, Fujisawa FK-973,fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin,herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, KyowaHakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa HakkoKT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji SeikaME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG,neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRIInternational NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin,rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, SnowBrand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SSPharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS PharmaceuticalSS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A,terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa HakkoUCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin.

Preferred antibiotic anticancer agents that may be used in the presentinvention include, but are not limited to, those identified in Table No.7 of U.S. Pat. No. 6,858,598, incorporated herein by reference.

A fourth family of antineoplastic agents which may be used incombination with the present invention consists of syntheticnucleosides. Several synthetic nucleosides have been identified thatexhibit anticancer activity. A well known nucleoside derivative withstrong anticancer activity is 5-fluorouracil (5-FU). 5-Fluorouracil hasbeen used clinically in the treatment of malignant tumors, including,for example, carcinomas, sarcomas, skin cancer, cancer of the digestiveorgans, and breast cancer. 5-Fluorouracil, however, causes seriousadverse reactions such as nausea, alopecia, diarrhea, stomatitis,leukocytic thrombocytopenia, anorexia, pigmentation, and edema.Derivatives of 5-fluorouracil with anti-cancer activity have beendescribed in U.S. Pat. No. 4,336,381. Further 5-FU derivatives have beendescribed in the following patents identified in Table No. 8 of U.S.Pat. No. 6,858,598, incorporated herein by reference.

U.S. Pat. No. 4,000,137 discloses that the peroxidate oxidation productof inosine, adenosine, or cytidine with methanol or ethanol has activityagainst lymphocytic leukemia. Cytosine arabinoside (also referred to asCytarabin, araC, and Cytosar) is a nucleoside analog of deoxycytidinethat was first synthesized in 1950 and introduced into clinical medicinein 1963. It is currently an important drug in the treatment of acutemyeloid leukemia. It is also active against acute lymphocytic leukemia,and to a lesser extent, is useful in chronic myelocytic leukemia andnon-Hodgkin's lymphoma. The primary action of araC is inhibition ofnuclear DNA synthesis. Handschumacher, R. and Cheng, Y., “Purine andPyrimidine Antimetabolites”, Cancer Medicine, Chapter XV-1, 3rd Edition,Edited by J. Holland, et al., Lea and Febigol, publishers.

5-Azacytidine is a cytidine analog that is primarily used in thetreatment of acute myelocytic leukemia and myelodysplastic syndrome.

2-Fluoroadenosine-5′-phosphate (Fludara, also referred to as FaraA) isone of the most active agents in the treatment of chronic lymphocyticleukemia. The compound acts by inhibiting DNA synthesis. Treatment ofcells with F-araA is associated with the accumulation of cells at theG1/S phase boundary and in S phase; thus, it is a cell cycle Sphase-specific drug. InCorp of the active metabolite, F-araATP, retardsDNA chain elongation. F-araA is also a potent inhibitor ofribonucleotide reductase, the key enzyme responsible for the formationof dATP. 2-Chlorodeoxyadenosine is useful in the treatment of low gradeB-cell neoplasms such as chronic lymphocytic leukemia, non-Hodgkins'lymphoma, and hairy-cell leukemia. The spectrum of activity is similarto that of Fludara. The compound inhibits DNA synthesis in growing cellsand inhibits DNA repair in resting cells.

A fifth family of antineoplastic agents which may be used in combinationwith the present invention consists of hormonal agents. Suitablehormonal-type antineoplastic agents that may be used in the presentinvention include, but are not limited to Abarelix; Abbott A-84861;Abiraterone acetate; Aminoglutethimide; anastrozole; Asta Medica AN-207;Antide; Chugai AG-041R; Avorelin; aseranox; Sensus B2036-PEG;Bicalutamide; buserelin; BTG CB-7598, BTG CB-7630; Casodex; cetrolix;clastroban; clodronate disodium; Cosudex; Rotta Research CR-1505;cytadren; crinone; deslorelin; droloxifene; dutasteride; Elimina; LavalUniversity EM-800; Laval University EM-652; epitiostanol; epristeride;Mediolanum EP-23904; EntreMed 2-ME; exemestane; fadrozole; finasteride;flutamide; formestane; Pharmacia & Upjohn FCE-24304; ganirelix;goserelin; Shire gonadorelin agonist; Glaxo Wellcome GW-5638; HoechstMarion Roussel Hoe-766; NCI hCG; idoxifene; isocordoin; ZenecaICI-182780; Zeneca ICI-118630; Tulane University J015X; Schering Ag J96;ketanserin; lanreotide; Milkhaus LDI-200; letrozol; leuprolide;leuprorelin; liarozole; lisuride hydrogen maleate; loxiglumide;mepitiostane; Leuprorelin; Ligand Pharmaceuticals LG-1127; LG-1447;LG-2293; LG-2527; LG-2716; Bone Care International LR-103; LillyLY-326315; Lilly LY-353381-HCl; Lilly LY-326391; Lilly LY-353381; LillyLY-357489; miproxifene phosphate; Orion Pharma MPV-2213ad; TulaneUniversity MZ-4-71; nafarelin; nilutamide; Snow Brand NKS01; octreotide;Azko Nobel ORG-31710; Azko Nobel ORG-31806; orimeten; orimetene;orimetine; ormeloxifene; osaterone; Smithkline Beecham SKB-105657; TokyoUniversity OSW-1; Peptech PTL-03001; Pharmacia & Upjohn PNU-156765;quinagolide; ramorelix; Raloxifene; statin; sandostatin LAR; ShionogiS-10364; Novartis SMT-487; somavert; somatostatin; tamoxifen; tamoxifenmethiodide; teverelix; toremifene; triptorelin; TT-232; vapreotide;vorozole; Yamanouchi YM-116; Yamanouchi YM-511; Yamanouchi YM-55208;Yamanouchi YM-53789; Schering AG ZK-1911703; Schering AG ZK-230211; andZeneca ZD-182780.

Preferred hormonal agents that may be used in the present inventioninclude, but are not limited to, those identified in Table No. 9 of U.S.Pat. No. 6,858,598, incorporated herein by reference.

A sixth family of antineoplastic agents which may be used in combinationwith the present invention consists of a miscellaneous family ofantineoplastic agents including, but not limited to alpha-carotene,alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52,alstonine, amonafide, amphethinile, amsacrine, Angiostat, ankinomycin,anti-neoplaston A10, antineoplaston A2, antineoplaston A3,antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolinglycinate, asparaginase, Avarol, baccharin, batracylin, benfluron,benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-MyersBMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, WellcomeBW-773, calcium carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane calciumcarbonate tablets, caracemide, carmethizole hydrochloride, AjinomotoCDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Cell Pathways CP-461, Yakult Honsha CPT-11,crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609,DABIS maleate, dacarbazine, datelliptinium, DFMO, didemnin-B,dihaematoporphyrin ether, dihydrolenperone dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel,Encore Pharmaceuticals E7869, elliprabin, elliptinium acetate, TsumuraEPMTC, ergotamine, etoposide, etretinate, Eulexin, Cell PathwaysExisulind (sulindac sulphone or CP-246), fenretinide, Merck ResearchLabs Finasteride, Florical, Fujisawa FR-57704, gallium nitrate,gemcitabine, genkwadaphnin, Gerimed, Chugai GLA-43, Glaxo GR-63178,grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221,homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, irinotecan,isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, ketoconazole,Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, AmericanCyanamid L-623, leucovorin, levamisole, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP, marycin,Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone, merocyaninederivatives, methylanilinoacridine, Molecular Genetics MGI-136,minactivin, mitonafide, mitoquidone, Monocal, mopidamol, motretinide,Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids, Nilandron;Nisshin Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom,Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative, Normosang,NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580,octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel,pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner-LambertPD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptideD, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin,probimane, procarbazine, proglumide, Invitron protease nexin I, TobishiRA-700, razoxane, retinoids, R-flurbiprofen (Encore Pharmaceuticals),Sandostatin; Sapporo Breweries RBS, restrictin-P, retelliptine, retinoicacid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Scherring-PloughSC-57050, Scherring-Plough SC-57068, selenium(selenite andselenomethionine), SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, Sugen SU-101, SugenSU-5416, Sugen SU-6668, sulindac, sulindac sulfone; superoxidedismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303,teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides,Yamanouchi YM-534, Zileuton, ursodeoxycholic acid, and Zanosar.

Preferred miscellaneous agents that may be used in the present inventioninclude, but are not limited to, those identified in (the second) TableNo. 6 of U.S. Pat. No. 6,858,598, incorporated herein by reference.

Some additional preferred antineoplastic agents include those describedin the individual patents listed in U.S. Pat. No. 6,858,598 in (thesecond) Table No. 7, and are hereby individually incorporated byreference.

In embodiments, the agent delivered by the balloon is a radiosensitizer,administered prior to radiation therapy. Radiosensitizers increasesensitivity to radiation, thereby allowing reduction of the radiationdosage.

An “antibiotic agent,” as used herein, is a substance or compound thatkills bacteria (i.e., is bacteriocidal) or inhibits the growth ofbacteria (i.e., is bacteriostatic).

Antibiotics that can be used in the devices and methods of the presentinvention include, but are not limited to, amikacin, amoxicillin,gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin,geldanamycin, herbimycin, carbacephem (loracarbef), ertapenem,doripenem, imipenem, cefadroxil, cefazolin, cefalotin, cephalexin,cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime,ceftobiprole, clarithromycin, clavulanic acid, clindamycin, teicoplanin,azithromycin, dirithromycin, erythromycin, troleandomycin,telithromycin, aztreonam, ampicillin, azlocillin, bacampicillin,carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin,meticillin, nafcillin, norfloxacin, oxacillin, penicillin G, penicillinV, piperacillin, pvampicillin, pivmecillinam, ticarcillin, bacitracin,colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin,levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, trovafloxacin,grepafloxacin, sparfloxacin, afenide, prontosil, sulfacetamide,sulfamethizole, sulfanilimide, sulfamethoxazole, sulfisoxazole,trimethoprim, trimethoprim-sulfamethoxazole, demeclocycline,doxycycline, oxytetracycline, tetracycline, arsphenamine,chloramphenicol, lincomycin, ethambutol, fosfomycin, furazolidone,isoniazid, linezolid, mupirocin, nitrofurantoin, platensimycin,pyrazinamide, quinupristin/dalfopristin, rifampin, thiamphenicol,rifampicin, minocycline, sultamicillin, sulbactam, sulphonamides,mitomycin, spectinomycin, spiramycin, roxithromycin, and meropenem.

Antibiotics can also be grouped into classes of related drugs, forexample, aminoglycosides (e.g., amikacin, gentamicin, kanamycin,neomycin, netilmicin, paromomycin, streptomycin, tobramycin), ansamycins(e.g., geldanamycin, herbimycin), carbacephem (loracarbef) carbapenems(e.g., ertapenem, doripenem, imipenem, meropenem), first generationcephalosporins (e.g., cefadroxil, cefazolin, cefalotin, cefalexin),second generation cephalosporins (e.g., cefaclor, cefamandole,cefoxitin, cefprozil, cefuroxime), third generation cephalosporins(e.g., cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone), fourthgeneration cephalosporins (e.g., cefepime), fifth generationcephalosporins (e.g., ceftobiprole), glycopeptides (e.g., teicoplanin,vancomycin), macrolides (e.g., azithromycin, clarithromycin,dirithromycin, erythromycin, roxithromycin, troleandomycin,telithromycin, spectinomycin), monobactams (e.g., aztreonam),penicillins (e.g., amoxicillin, ampicillin, azlocillin, bacampicillin,carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin,meticillin, nafcillin, oxacillin, penicillins G and V, piperacillin,pvampicillin, pivmecillinam, ticarcillin), polypeptides (e.g.,bacitracin, colistin, polymyxin B), quinolones (e.g., ciprofloxacin,enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin,trovafloxacin), sulfonamides (e.g., afenide, prontosil, sulfacetamide,sulfamethizole, sulfanilimide, sulfasalazine, sulfamethoxazole,sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole),tetracyclines (e.g., demeclocycline, doxycycline, minocycline,oxytetracycline, tetracycline).

For treatment of abcesses, commonly caused by Staphylococcus aureusbacteria, use of an anti-staphylococcus antibiotic such asflucloxacillin or dicloxacillin is contemplated. With the emergence ofcommunity-acquired methicillin-resistant staphylococcus aureus MRSA,these traditional antibiotics may be ineffective; alternativeantibiotics effective against community-acquired MRSA often includeclindamycin, trimethoprim-sulfamethoxazole, and doxycycline. Theseantibiotics may also be prescribed to patients with a documented allergyto penicillin. If the condition is thought to be cellulitis rather thanabscess, consideration should be given to possibility of strep speciesas cause that are still sensitive to traditional anti-staphylococcusagents such as dicloxacillin or cephalexin in patients able to toleratepenicillin.

Anti-thrombotic agents are contemplated for use in the methods of theinvention in adjunctive therapy for treatment of coronary stenosis. Theuse of anti-platelet drugs, e.g., to prevent platelet binding to exposedcollagen, is contemplated for anti-restenotic or anti-thrombotictherapy. Anti-platelet agents include “GpIIb/IIIa inhibitors” (e.g.,abciximab, eptifibatide, tirofiban, RheoPro) and “ADP receptor blockers”(prasugrel, clopidogrel, ticlopidine). Particularly useful for localtherapy are dipyridamole, which has local vascular effects that improveendothelial function (e.g., by causing local release of t-PA, that willbreak up clots or prevent clot formation) and reduce the likelihood ofplatelets and inflammatory cells binding to damaged endothelium, andcAMP phosphodiesterase inhibitors, e.g., cilostazol, that could bind toreceptors on either injured endothelial cells or bound and injuredplatelets to prevent further platelet binding.

The methods of the invention are useful for encouraging migration andproliferation of endothelial cells from adjacent vascular domains to“heal” the damaged endothelium and/or encourage homing and maturation ofblood-borne endothelial progenitor cells to the site of injury. There isevidence that both rapamycin and paclitaxel prevent endothelial cellgrowth and reduce the colonization and maturation of endothelialprogenitor cells (EPCs) making both drugs ‘anti-healing.’ While localdelivery of growth factors could accelerate endothelial cell regrowth,virtually all of these agents are equally effective at accelerating theproliferation of vascular smooth muscle cells, which can causerestenosis. VEGF is also not selective for endothelial cells but cancause proliferation of smooth muscle cells. To make VEGF more selectivefor endothelial cells it can be combined with a proteoglycan likeheparan sulfate or chondroitin sulfate or even with an elongated “RGD”peptide binding domain. This may sequester it away from the actuallesion site but still allow it to dissociate and interact with nearbyendothelial cells. The use of CD34 antibodies and other specificantibodies, which bind to the surface of blood borne progenitor cells,can be used to attract endothelial progenitor cells to the vessel wallto potential accelerate endothelialization.

Statins (e.g., cerivastatin, etorvastatin), which can have endothelialprotective effects and improve progenitor cell function, arecontemplated for use in embodiments of methods and/or devices providedherein. Other drugs that have demonstrated some evidence to improve EPCcolonization, maturation or function and are contemplated for use in themethods of the invention are angiotensin converting enzyme inhibitors(ACE-I, e.g., Captopril, Enalapril, and Ramipril), Angiotensin II type Ireceptor blockers (AT-II-blockers, e.g., losartan, valartan), peroxisomeproliferator-activated receptor gamma (PPAR-γ) agonists, anderythropoietin. The PPAR-γ agonists like the glitazones (e.g.,rosiglitazone, pioglitazone) can provide useful vascular effects,including the ability to inhibit vascular smooth muscle cellproliferation, and have anti-inflammatory functions, localantithrombotic properties, local lipid lowing effects, and can inhibitmatrix metalloproteinase (MMP) activity so as to stabilize vulnerableplaque.

Atherosclerosis is viewed as a systemic disease with significant localevents. Adjunctive local therapy can be used in addition to systemictherapy to treat particularly vulnerable areas of the vascular anatomy.The mutant protein Apo A1 Milano has been reported to remove unwantedlipid from a blood vessel and can cause regression of atherosclerosis.Either protein therapy, or gene therapy to provide sustained release ofa protein therapy, can be delivered using the methods of the invention.Adiponectin, a protein produced by adipocytes, is another protein withanti-atherosclerotic properties. It prevents inflammatory cell bindingand promotes generation of nitric oxide (NO). NO has been shown to haveantiatherogenic activity in the vessel wall; it promotesantiinflammatory and other beneficial effects. The use of agentsincluding nitric oxide synthase (NOS) gene therapy that act to increaseNO levels, are contemplated herein. NOS gene therapy is described, e.g.,by Channon, et al., 2000, “Nitric Oxide Synthase in Atherosclerosis andVascular Injury: Insights from Experimental Gene Therapy,”Arteriosclerosis, Thrombosis, and Vascular Biology, 20(8):1873-1881.Compounds for treating NO deficiency are described, e.g., in U.S. Pat.No. 7,537,785, “Composition for treating vascular diseases characterizedby nitric oxide insufficiency,” incorporated herein by reference in itsentirety. “Vulnerable plaque” occurs in blood vessels where a pool oflipid lies below a thin fibrous cap. If the cap ruptures then the highlythrombogenic lipid leaks into the artery often resulting in abruptclosure of the vessel due to rapid clotting. Depending on the locationof the vulnerable plaque, rupture can lead to sudden death. Both statinsand glitazones have been shown to strengthen the fibrous cap coveringthe plaque and make it less vulnerable. Other agents, e.g., batimastator marimastat, target the MMPs that can destroy the fibrin cap.

Angiogenesis promoters can be used for treating reperfusion injury,which can occur when severely stenotic arteries, particular chronictotal occlusions, are opened. Angiogenesis promoters are contemplatedfor use in embodiments of methods and/or devices provided herein.Myocardial cells downstream from a blocked artery will downregulate thepathways normally used to prevent damage from oxygen free radicals andother blood borne toxins. A sudden infusion of oxygen can lead toirreversible cell damage and death. Drugs developed to prevent thisphenomenon can be effective if provided by sustained local delivery.Neurovascular interventions can particularly benefit from this treatmentstrategy. Examples of pharmacological agents potentially useful inpreventing reperfusion injury are glucagon-like peptide 1,erythropoietin, atorvastatin, and atrial natriuretic peptide (ANP).Other angiogenesis promoters have been described, e.g., in U.S. Pat. No.6,284,758, “Angiogenesis promoters and angiogenesis potentiators,” U.S.Pat. No. 7,462,593, “Compositions and methods for promotingangiogenesis,” and U.S. Pat. No. 7,456,151, “Promoting angiogenesis withnetrin1 polypeptides.”

“Local anesthetics” are substances which inhibit pain signals in alocalized region. Examples of such anesthetics include procaine,lidocaine, tetracaine and dibucaine. Local anesthetics are contemplatedfor use in embodiments of methods and/or devices provided herein.

“Anti-inflammatory agents” as used herein refer to agents used to reduceinflammation. Anti-inflammatory agents useful in the devices and methodsof the invention include, but are not limited to: aspirin, ibuprofen,naproxen, hyssop, ginger, turmeric, helenalin, cannabichromene,rofecoxib, celecoxib, paracetamol (acetaminophen), sirolimus(rapamycin), dexamethasone, dipyridamole, alfuzosin, statins, andglitazones. Antiinflammatory agents are contemplated for use inembodiments of methods and/or devices provided herein.

Antiinflammatory agents can be classified by action. For example,glucocorticoids are steroids that reduce inflammation or swelling bybinding to cortisol receptors. Non-steroidal anti-inflammatory drugs(NSAIDs), alleviate pain by acting on the cyclooxygenase (COX) enzyme.COX synthesizes prostaglandins, causing inflammation. A cannabinoid,cannabichromene, present in the cannabis plant, has been reported toreduce inflammation. Newer COX-inhibitors, e.g., rofecoxib andcelecoxib, are also antiinflammatory agents. Many antiinflammatoryagents are also analgesics (painkillers), including salicylic acid,paracetamol (acetaminophen), COX-2 inhibitors and NSAIDs. Also includedamong analgesics are, e.g., narcotic drugs such as morphine, andsynthetic drugs with narcotic properties such as tramadol.

Other antiinflammatory agents useful in the methods of the presentinvention include sirolimus (rapamycin) and dexamethasone. Stents coatedwith dexamethasone were reported to be useful in a particular subset ofpatients with exaggerated inflammatory disease evidenced by high plasmaC-reactive protein levels. Because both restenosis and atherosclerosishave such a large inflammatory component, anti-inflammatories remain ofinterest with regard to local therapeutic agents. In particular, the useof agents that have anti-inflammatory activity in addition to otheruseful pharmacologic actions is contemplated. Examples includedipyridamole, statins and glitazones. Despite an increase incardiovascular risk and systemic adverse events reported with use ofcyclooxygenase (COX)-inhibitors (e.g., celocoxib), these drugs can beuseful for short term local therapy.

“Stability” as used herein in refers to the stability of the drug in acoating deposited on a substrate in its final product form (e.g.,stability of the drug in a coated stent). The term “stability” and/or“stable” in some embodiments is defined by 5% or less degradation of thedrug in the final product form. The term stability in some embodimentsis defined by 3% or less degradation of the drug in the final productform. The term stability in some embodiments is defined by 2% or lessdegradation of the drug in the final product form. The term stability insome embodiments is defined by 1% or less degradation of the drug in thefinal product form.

In some embodiments, the pharmaceutical agent is at least one of: 50%crystalline, 75% crystalline, 80% crystalline, 90% crystalline, 95%crystalline, 97% crystalline, and 99% crystalline followingsterilization of the device. In some embodiments, the pharmaceuticalagent crystallinity is stable wherein the crystallinity of thepharmaceutical agent following sterilization is compared to thecrystallinity of the pharmaceutical agent at least one of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In some embodiments, the pharmaceutical agentcrystallinity is stable wherein the crystallinity of the pharmaceuticalagent prior to sterilization is compared to the crystallinity of thepharmaceutical agent at least one of: 1 week after sterilization, 2weeks after sterilization, 4 weeks after sterilization, 1 month aftersterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization. In such embodiments, different devices may be tested fromthe same manufacturing lot to determine stability of the pharmaceuticalagent at the desired time points.

In some embodiments, the pharmaceutical agent crystallinity is stable atat least one of: 1 week after sterilization, 2 weeks aftersterilization, 4 weeks after sterilization, 1 month after sterilization,2 months after sterilization, 45 days after sterilization, 60 days aftersterilization, 90 days after sterilization, 3 months aftersterilization, 4 months after sterilization, 6 months aftersterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, and 2 years aftersterilization.

In some embodiments, the pharmaceutical agent crystallinity on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity tested on a seconddevice manufactured from the same lot of devices and the same lot ofpharmaceutical agent at testing time point before sterilization (i.e.the crystallinity drops no more than from 99 to 94% crystalline, forexample, which is a 5% difference in crystallinity; the crystallinitydrops no more than from 99 to 95% crystalline, which is a 4% differencein crystallinity; the crystallinity drops no more than from 99 to 96%crystalline, for example, which is a 3% difference in crystallinity; thecrystallinity drops no more than from 99 to 97% crystalline, forexample, which is a 2% difference in crystallinity; the crystallinitydrops no more than from 99 to 98% crystalline, for example, which is a1% difference in crystallinity; in other examples, the startingcrystallinity percentage is one of 100%, 98%, 96%, 97%, 96%, 95%, 90%,85%, 80%, 75%, 70%, 60%, 50%, 30%, 25%, and/or anything in between).

In some embodiments, crystallinity of the pharmaceutical agent on thedevice tested at a time point after sterilization does not differ morethan 1%, 2%, 3%, 4%, and/or 5% from the crystallinity of pharmaceuticalfrom the same lot of pharmaceutical agent tested at testing time pointbefore sterilization of the pharmaceutical agent.

In some embodiments, crystallinity of the pharmaceutical agent does notdrop more than 1%, 2%, 3%, 4%, and/or 5% between two testing time pointsafter sterilization neither of which time point being greater than 2years after sterilization. In some embodiments, crystallinity of thepharmaceutical agent does not drop more than 1%, 2%, 3%, 4%, and/or 5%between two testing time points after sterilization neither of whichtime point being greater than 5 years after sterilization. In someembodiments, two time points comprise two of: 1 week aftersterilization, 2 weeks after sterilization, 4 weeks after sterilization,1 month after sterilization, 2 months after sterilization, 45 days aftersterilization, 60 days after sterilization, 90 days after sterilization,3 months after sterilization, 4 months after sterilization, 6 monthsafter sterilization, 9 months after sterilization, 12 months aftersterilization, 18 months after sterilization, 2 years aftersterilization, 3 years after sterilization, 4 years after sterilization,and 5 years after sterilization.

“Active biological agent” as used herein refers to a substance,originally produced by living organisms, that can be used to prevent ortreat a disease (meaning any treatment of a disease in a mammal,including preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop; inhibiting the disease, i.e. arresting thedevelopment of clinical symptoms; and/or relieving the disease, i.e.causing the regression of clinical symptoms). It is possible that theactive biological agents of the invention may also comprise two or moreactive biological agents or an active biological agent combined with apharmaceutical agent, a stabilizing agent or chemical or biologicalentity. Although the active biological agent may have been originallyproduced by living organisms, those of the present invention may alsohave been synthetically prepared, or by methods combining biologicalisolation and synthetic modification. By way of a non-limiting example,a nucleic acid could be isolated form from a biological source, orprepared by traditional techniques, known to those skilled in the art ofnucleic acid synthesis. Furthermore, the nucleic acid may be furthermodified to contain non-naturally occurring moieties. Non-limitingexamples of active biological agents include growth factors, cytokines,peptides, proteins, enzymes, glycoproteins, nucleic acids (includingdeoxyribonucleotide or ribonucleotide polymers in either single ordouble stranded form, and unless otherwise limited, encompasses knownanalogues of natural nucleotides that hybridize to nucleic acids in amanner similar to naturally occurring nucleotides), antisense nucleicacids, fatty acids, antimicrobials, vitamins, hormones, steroids,lipids, polysaccharides, carbohydrates and the like. They furtherinclude, but are not limited to, antirestenotic agents, antidiabetics,analgesics, antiinflammatory agents, antirheumatics, antihypotensiveagents, antihypertensive agents, psychoactive drugs, tranquillizers,antiemetics, muscle relaxants, glucocorticoids, agents for treatingulcerative colitis or Crohn's disease, antiallergics, antibiotics,antiepileptics, anticoagulants, antimycotics, antitussives,arteriosclerosis remedies, diuretics, proteins, peptides, enzymes,enzyme inhibitors, gout remedies, hormones and inhibitors thereof,cardiac glycosides, immunotherapeutic agents and cytokines, laxatives,lipid-lowering agents, migraine remedies, mineral products, otologicals,anti parkinson agents, thyroid therapeutic agents, spasmolytics,platelet aggregation inhibitors, vitamins, cytostatics and metastasisinhibitors, phytopharmaceuticals and chemotherapeutic agents.Preferably, the active biological agent is a peptide, protein or enzyme,including derivatives and analogs of natural peptides, proteins andenzymes. The active biological agent may also be a hormone, genetherapies, RNA, siRNA, and/or cellular therapies (for non-limitingexample, stem cells or T-cells).

It is understood that certain agents will fall into multiple categoriesof agents, for example, certain antibiotic agents are alsochemotherapeutic agents, and biological agents can include antibioticagents, etc.

Specific pharmaceutical agents useful in certain embodiments of devicesand/or methods of the invention are hyaluronidases. Hylenex (BaxterInternational, Inc.) is a formulation of a human recombinanthyaluronidase, PH-20, that is used to facilitate the absorption anddispersion of other injected drugs or fluids. When injected under theskin or in the muscle, hyaluronidase can digest the hyaluronic acid gel,allowing for temporarily enhanced penetration and dispersion of otherinjected drugs or fluids.

Hyaluronidase can allow drugs to pass more freely to target tissues. Ithas been observed on its own to suppress tumor growth, and is thus achemotherapeutic agent. For example, increased drug antitumor activityhas been reported by Halozyme Therapeutics (Carlsbad, Calif.), whenhyaluronidase is used in conjunction with another chemotherapeutic agentto treat an HA-producing tumor (reports available athttp://www.halozyme.com). A pegylated hyaluronidase product (PEGPH20) iscurrently being tested as a treatment for prostate cancer, and a productcontaining both hyaluronidase and mitomycin C (Chemophase) is beingtested for treatment of bladder cancer.

In certain embodiments of devices and/or methods provided herein,hyaluronidase is used for treating any HA-producing cancer, either aloneor in combination with another chemotherapeutic agent. In particularembodiments, hyaluronidase is used in the methods of the invention fortreating bladder cancer, e.g., in combination with mitomycin C. In otherembodiments, hyaluronidase is used for treating prostate cancer. Cancerspotentially treated with hyaluronidase include, but are not limited to,Kaposi's sarcoma, glioma, melanocyte, head and neck squamous cellcarcinoma, breast cancer, gastrointestinal cancer, and othergenitourinary cancers, e.g., testicular cancer and ovarian cancer. Thecorrelation of HA with various cancers has been described in theliterature, e.g., by Simpson, et al., Front Biosci. 13:5664-5680. Inembodiments, hyaluronidase is used in the devices and methods of theinvention to enhance penetration and dispersion of any agents describedherein, including, e.g., painkillers, antiinflammatory agents, etc., inparticular, to tissues that produce HA.

Hyaluronidases are described, e.g., in U.S. Pat. App. No. 2005/0260186and 2006/0104968, both titled “Soluble glycosaminoglycanases and methodsof preparing and using soluble glycosaminoglycanases” and incorporatedherein by reference in their entirety. Bookbinder, et al., 2006, “Arecombinant human enzyme for enhanced interstitial transport oftherapeutics,” Journal of Controlled Release 114:230-241 reportedimproved pharmacokinetic profile and absolute bioavailability, ofpeginterferon alpha-2b or the antiinflammatory agent infliximab, wheneither one is coinjected with rHuPH20 (human recombinant hyaluronidasePH-20). They also reported that an increased volume of drug could beinjected subcutaneously when coinjected with hyaluronidase. Methods forproviding human plasma hyaluronidases, and assays for hyaluronidases,are described in, e.g., U.S. Pat. No. 7,148,201, “Use of human plasmahyaluronidase in cancer treatment,” incorporated herein by reference inits entirety. The use of hyaluronidase in the devices and methods of theinvention is expected to increase the rate and amount of drug absorbed,providing an added aspect to control over release rates.

Hyaluronidase co-delivery is also useful when an agent is administeredusing the devices and methods of the invention within a tissue nothaving a well-defined preexisting cavity or having a cavity that issmaller than the inflated delivery balloon. In these embodiments,inflation of the delivery balloon creates a cavity where either noneexisted or greatly enlarges an existing cavity. For example, a solidtumor can be treated with hyaluronidase and a chemotherapeutic agentusing a delivery balloon inserted through, e.g., a biopsy needle or thelike. Vasoactive agents, e.g., TNF-alpha and histamine, also can be usedto improve drug distribution within the tumor tissue. (See, e.g.,Brunstein, et al., 2006, “Histamine, a vasoactive agent with vasculardisrupting potential improves tumour response by enhancing local drugdelivery,” British Journal of Cancer 95:1663-1669). As another exampleof treatment of a location lacking a preexisting cavity, dense muscletissue can be treated locally with a slow-release painkiller, using adelivery balloon inserted through a hollow needle.

“Active agent” as used herein refers to any pharmaceutical agent oractive biological agent as described herein. An active agent, in someembodiments, may comprise a polymer, wherein the polymer provides adesired treatment in the body.

“Activity” as used herein refers to the ability of a pharmaceutical oractive biological agent to prevent or treat a disease (meaning anytreatment of a disease in a mammal, including preventing the disease,i.e. causing the clinical symptoms of the disease not to develop;inhibiting the disease, i.e. arresting the development of clinicalsymptoms; and/or relieving the disease, i.e. causing the regression ofclinical symptoms). Thus the activity of a pharmaceutical or activebiological agent should be of therapeutic or prophylactic value.

“Secondary, tertiary and quaternary structure” as used herein aredefined as follows. The active biological agents of the presentinvention will typically possess some degree of secondary, tertiaryand/or quaternary structure, upon which the activity of the agentdepends. As an illustrative, non-limiting example, proteins possesssecondary, tertiary and quaternary structure. Secondary structure refersto the spatial arrangement of amino acid residues that are near oneanother in the linear sequence. The α-helix and the β-strand areelements of secondary structure. Tertiary structure refers to thespatial arrangement of amino acid residues that are far apart in thelinear sequence and to the pattern of disulfide bonds. Proteinscontaining more than one polypeptide chain exhibit an additional levelof structural organization. Each polypeptide chain in such a protein iscalled a subunit. Quaternary structure refers to the spatial arrangementof subunits and the nature of their contacts. For example hemoglobinconsists of two α and two β chains. It is well known that proteinfunction arises from its conformation or three dimensional arrangementof atoms (a stretched out polypeptide chain is devoid of activity). Thusone aspect of the present invention is to manipulate active biologicalagents, while being careful to maintain their conformation, so as not tolose their therapeutic activity.

“Polymer” as used herein, refers to a series of repeating monomericunits that have been cross-linked or polymerized. Any suitable polymercan be used to carry out the present invention. It is possible that thepolymers of the invention may also comprise two, three, four or moredifferent polymers. In some embodiments of the invention only onepolymer is used. In certain embodiments a combination of two polymers isused. Combinations of polymers can be in varying ratios, to providecoatings with differing properties. Polymers useful in the devices andmethods of the present invention include, for example, stable or inertpolymers, organic polymers, organic-inorganic copolymers, inorganicpolymers, bioabsorbable, bioresorbable, resorbable, degradable, andbiodegradable polymers. Those of skill in the art of polymer chemistrywill be familiar with the different properties of polymeric compounds.

In some embodiments, the coating further comprises a polymer. In someembodiments, the active agent comprises a polymer. In some embodiments,the polymer comprises at least one of polyalkyl methacrylates,polyalkylene-co-vinyl acetates, polyalkylenes, polyurethanes,polyanhydrides, aliphatic polycarbonates, polyhydroxyalkanoates,silicone containing polymers, polyalkyl siloxanes, aliphatic polyesters,polyglycolides, polylactides, polylactide-co-glycolides,poly(e-caprolactone)s, polytetrahalooalkylenes, polystyrenes,poly(phosphasones), copolymers thereof, and combinations thereof.

In embodiments, the polymer is capable of becoming soft afterimplantation, for example, due to hydration, degradation or by acombination of hydration and degradation. In embodiments, the polymer isadapted to transfer, free, and/or dissociate from the substrate when atthe intervention site due to hydrolysis of the polymer. In variousembodiments, the device is coated with a bioabsorbable polymer that iscapable of resorbtion in at least one of: about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

Examples of polymers that may be used in the present invention include,but are not limited to polycarboxylic acids, cellulosic polymers,proteins, polypeptides, polyvinylpyrrolidone, maleic anhydride polymers,polyamides, polyvinyl alcohols, polyethylene oxides, glycosaminoglycans,polysaccharides, polyesters, aliphatic polyesters, polyurethanes,polystyrenes, copolymers, silicones, silicone containing polymers,polyalkyl siloxanes, polyorthoesters, polyanhydrides, copolymers ofvinyl monomers, polycarbonates, polyethylenes, polypropytenes,polylactic acids, polylactides, polyglycolic acids, polyglycolides,polylactide-co-glycolides, polycaprolactones, poly(e-caprolactone)s,polyhydroxybutyrate valerates, polyacrylamides, polyethers, polyurethanedispersions, polyacrylates, acrylic latex dispersions, polyacrylic acid,polyalkyl methacrylates, polyalkylene-co-vinyl acetates, polyalkylenes,aliphatic polycarbonates polyhydroxyalkanoates, polytetrahalooalkylenes,poly(phosphasones), polytetrahalooalkylenes, poly(phosphasones), andmixtures, combinations, and copolymers thereof.

The polymers of the present invention may be natural or synthetic inorigin, including gelatin, chitosan, dextrin, cyclodextrin,Poly(urethanes), Poly(siloxanes) or silicones, Poly(acrylates) such as[rho]oly(methyl methacrylate), poly(butyl methacrylate), andPoly(2-hydroxy ethyl methacrylate), Poly(vinyl alcohol) Poly(olefins)such as poly(ethylene), [rho]oly(isoprene), halogenated polymers such asPoly(tetrafluoroethylene)—and derivatives and copolymers such as thosecommonly sold as Teflon® products, Poly(vinylidine fluoride), Poly(vinylacetate), Poly(vinyl pyrrolidone), Poly(acrylic acid), Polyacrylamide,Poly(ethylene-co-vinyl acetate), Poly(ethylene glycol), Poly(propyleneglycol), Poly(methacrylic acid); etc.

Suitable polymers also include absorbable and/or resorbable polymersincluding the following, combinations, copolymers and derivatives of thefollowing: Polylactides (PLA), Polyglycolides (PGA),PolyLactide-co-glycolides (PLGA), Polyanhydrides, Polyorthoesters,Poly(N-(2-hydroxypropyl) methacrylamide), Poly(1-aspartamide), includingthe derivatives DLPLA—poly(dl-lactide); LPLA—poly(1-lactide);PDO—poly(dioxanone); PGA-TMC—poly(glycolide-co-trimethylene carbonate);PGA-LPLA—poly(1-lactide-co-glycolide);PGA-DLPLA—poly(dl-lactide-co-glycolide);LPLA-DLPLA—poly(1-lactide-co-dl-lactide); andPDO-PGA-TMC—poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations thereof.

“Copolymer” as used herein refers to a polymer being composed of two ormore different monomers. A copolymer may also and/or alternatively referto random, block, graft, copolymers known to those of skill in the art.

The term “image enhanced polymer” or “imaging agent” as used hereinrefer to an agent that can be used with the devices and methods of theinvention to view at least one component of the coating, either whilethe coating is on the substrate or after it is freed, dissociated and/ortransferred. In embodiments, an image enhanced polymer serves as atracer, allowing the movement or location of the coated device to beidentified, e.g., using an imaging system. In other embodiments, animage enhanced polymer allows the practitioner to monitor the deliveryand movement of a coating component. In embodiments, use of an imageenhanced polymer enables the practitioner to determine the dose of acomponent of the coating (e.g., the active agent) that is freed,dissociated and/or transferred. Information provided by the imageenhanced polymer or imaging agent about the amount of coatingtransferred to the intervention site can allow the practitioner todetermine the rate at which the coating will be released, therebyallowing prediction of dosing over time. Imaging agents may comprisebarium compounds such as, for non-limiting example, barium sulfate.Imaging agents may comprise iodine compounds. Imaging agents maycomprise any compound that improves radiopacity.

In embodiments, an image enhanced polymer is used with the device andmethods of the invention for a purpose including, but not limited to,one or more of the following: monitoring the location of the substrate,e.g., a balloon or other device; assessing physiological parameters,e.g., flow and perfusion; and targeting to a specific molecule. Inembodiments, “smart” agents that activate only in the presence of theirintended target are used with the device and methods of the invention.

In embodiments, imaging agents useful with the device and methods of thepresent invention include, for example: EgadMe (in which agalactopyranose ring is synthesized to protect a Gd(III) ion from bulkwater); conjugated polymer MEH-PPV nanoparticles; bismuth trioxide; nearinfrared (NIR) fluorochromes; bioluminescence agents (e.g., greenfluorescent protein, red fluorescent protein); SPECT radionuclides,e.g., 99Tcm (6 h), 111In (2.8 days), 123I (13.2 h) and 125I (59.5 days);PET radionuclides, e.g., 15O (2.07 min), 13N (10 min), 11C (20.3 min),18F (1.83 h), 124I (4.2 days) and 94Tcm (53 min); Gd-DTPA (gadoliniumdiethylenetriamine pentaacetic acid); Echo-Coat, an ultrasound imagingagent (STS-Biopolymers); and barium sulfate. In embodiments employingnanoparticles, it is important that the particles are small enough toallow renal clearance (e.g. have a hydrodynamic diameter less than 5.5nm) and contain non-toxic components, and that the materialdecomposition products can be eliminated from the body. It is understoodthat an imaging agent can be conjugated or otherwise attached orassociated with a compound in the coating according to methods known tothose of skill in the art to form an image enhanced polymer.

Biological imaging agents useful in embodiments of the device andmethods of the present invention are described in, e.g.: U.S. Pat. No.6,077,880, “Highly radiopaque polyolefins and method for making thesame,” which sets forth a highly radiopaque polyolefin; U.S. Pat. No.7,229,837, “Enhanced photophysics of conjugated polymers,” relating tofluorescent ionic conjugated polymers; Dzik-Jurasz, 2003, “Molecularimaging in vivo: an introduction,” The British Journal of Radiology, 76:S98-S109, providing an overview of in vivo molecular imaging methods;von zur Muhlen, et al., 2008, Magnetic Resonance Imaging Contrast AgentTargeted Toward Activated Platelets Allows In Vivo Detection ofThrombosis and Monitoring of Thrombolysis Circulation,” 118:258-267,reporting imaging of activated platelets using an antibody-containingMRI imaging agent; and Green, et al., “Simple conjugated polymernanoparticles as biological labels,” Proc. Roy. Soc. A, published online24 Jun. 2009 doi: 10.1098/rspa.2009.0181, describing the use ofnanoparticles of conjugated polymers in biological imaging; allincorporated herein by reference in their entirety.

“Biocompatible” as used herein, refers to any material that does notcause injury or death to the animal or induce an adverse reaction in ananimal when placed in intimate contact with the animal's tissues.Adverse reactions include for example inflammation, infection, fibrotictissue formation, cell death, or thrombosis. The terms “biocompatible”and “biocompatibility” when used herein are art-recognized and mean thatthe referent is neither itself toxic to a host (e.g., an animal orhuman), nor degrades (if it degrades) at a rate that produces byproducts(e.g., monomeric or oligomeric subunits or other byproducts) at toxicconcentrations, causes inflammation or irritation, or induces an immunereaction in the host. It is not necessary that any subject compositionhave a purity of 100% to be deemed biocompatible. Hence, a subjectcomposition may comprise 99%, 98%, 97%, 96%, 95%, 90% 85%, 80%, 75% oreven less of biocompatible agents, e.g., including polymers and othermaterials and excipients described herein, and still be biocompatible.“Non-biocompatible” as used herein, refers to any material that maycause injury or death to the animal or induce an adverse reaction in theanimal when placed in intimate contact with the animal's tissues. Suchadverse reactions are as noted above, for example.

To determine whether a polymer or other material is biocompatible, itmay be necessary to conduct a toxicity analysis. Such assays are wellknown in the art. One example of such an assay may be performed withlive carcinoma cells, such as GT3TKB tumor cells, in the followingmanner: the sample is degraded in 1 M NaOH at 37 degrees C. untilcomplete degradation is observed. The solution is then neutralized with1 M HCl. About 200 microliters of various concentrations of the degradedsample products are placed in 96-well tissue culture plates and seededwith human gastric carcinoma cells (GT3TKB) at 104/well density. Thedegraded sample products are incubated with the GT3TKB cells for 48hours. The results of the assay may be plotted as % relative growth vs.concentration of degraded sample in the tissue-culture well. Inaddition, polymers and formulations of the present invention may also beevaluated by well-known in vivo tests, such as subcutaneousimplantations in rats to confirm that they do not cause significantlevels of irritation or inflammation at the subcutaneous implantationsites.

The terms “bioabsorbable,” “biodegradable,” “bioerodible,”“bioresorbable,” and “resorbable” are art-recognized synonyms. Theseterms are used herein interchangeably. Bioabsorbable polymers typicallydiffer from non-bioabsorbable polymers in that the former may beabsorbed (e.g.; degraded) during use. In certain embodiments, such useinvolves in vivo use, such as in vivo therapy, and in other certainembodiments, such use involves in vitro use. In general, degradationattributable to biodegradability involves the degradation of abioabsorbable polymer into its component subunits, or digestion, e.g.,by a biochemical process, of the polymer into smaller, non-polymericsubunits. In certain embodiments, biodegradation may occur by enzymaticmediation, degradation in the presence of water (hydrolysis) and/orother chemical species in the body, or both. The bioabsorbability of apolymer may be shown in-vitro as described herein or by methods known toone of skill in the art. An in-vitro test for bioabsorbability of apolymer does not require living cells or other biologic materials toshow bioabsorption properties (e.g. degradation, digestion). Thus,resorbtion, resorption, absorption, absorbtion, erosion may also be usedsynonymously with the terms “bioabsorbable,” “biodegradable,”“bioerodible,” and “bioresorbable.” Mechanisms of degradation of abioaborbable polymer may include, but are not limited to, bulkdegradation, surface erosion, and combinations thereof.

As used herein, the term “biodegradation” encompasses both general typesof biodegradation. The degradation rate of a biodegradable polymer oftendepends in part on a variety of factors, including the chemical identityof the linkage responsible for any degradation, the molecular weight,crystallinity, biostability, and degree of cross-linking of suchpolymer, the physical characteristics (e.g., shape and size) of theimplant, and the mode and location of administration. For example, thegreater the molecular weight, the higher the degree of crystallinity,and/or the greater the biostability, the biodegradation of anybioabsorbable polymer is usually slower.

In some embodiments, the coating comprises a biodegradable material thatis adhered and/or cohered to the substrate prior to implantation,wherein the biodegradable material is capable of degrading over time tolose its cohesion and/or adhesion to the substrate. In some embodiments,the pharmaceutical agent and/or the active agent is released from thecoating within at least one of about 1 day, about 3 days, about 5 days,about 7 days, about 14 days, about 3 weeks, about 4 weeks, about 45days, about 60 days, about 90 days, about 180 days, about 6 months,about 9 months, about 1 year, about 1 to about 2 days, about 1 to about5 days, about 1 to about 2 weeks, about 2 about 4 weeks, about 45 toabout 60 days, about 45 to about 90 days, about 30 to about 90 days,about 60 to about 90 days, about 90 to about 180 days, about 60 to about180 days, about 180 to about 365 days, about 6 months to about 9 months,about 9 months to about 12 months, about 9 months to about 15 months,and about 1 year to about 2 years.

“Hydration” as used herein refers to the absorption of water by asubstance, or the combination of a substance with water. Hydration ofthe coating may reduce the coating's cohesive and adhesive binding tothe device, thereby facilitating transfer of the coating to theintervention site.

“Hydrolysis” as used herein refers to a chemical reaction in which waterreacts with a compound to produce other compounds; involves thesplitting of a bond and the addition of the hydrogen cation and thehydroxide anion from the waterImage enhanced polymer, imaging agent.

“Degradation” as used herein refers to the conversion or reduction of achemical compound to one less complex, e.g., by splitting off one ormore groups of atoms. Degradation of the coating may reduce thecoating's cohesive and adhesive binding to the device, therebyfacilitating transfer of the coating to the intervention site.

“Therapeutically desirable morphology” as used herein refers to thegross form and structure of the pharmaceutical agent, once deposited onthe substrate, so as to provide for optimal conditions of ex vivostorage, in vivo preservation and/or in vivo release. Such optimalconditions may include, but are not limited to increased shelf life(i.e., shelf stability), increased in vivo stability, goodbiocompatibility, good bioavailability or modified release rates.Typically, for the present invention, the desired morphology of apharmaceutical agent would be crystalline or semi-crystalline oramorphous, although this may vary widely depending on many factorsincluding, but not limited to, the nature of the pharmaceutical agent,the disease to be treated/prevented, the intended storage conditions forthe substrate prior to use or the location within the body of anybiomedical implant. Preferably at least 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, and/or 100% of thepharmaceutical agent is in crystalline or semi-crystalline form.

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

“Stabilizing agent” as used herein refers to any substance thatmaintains or enhances the stability of the biological agent. Ideallythese stabilizing agents are classified as Generally Regarded As Safe(GRAS) materials by the US Food and Drug Administration (FDA). Examplesof stabilizing agents include, but are not limited to carrier proteins,such as albumin, gelatin, metals or inorganic salts. Pharmaceuticallyacceptable excipient that may be present can further be found in therelevant literature, for example in the Handbook of PharmaceuticalAdditives: An International Guide to More Than 6000 Products by TradeName, Chemical, Function, and Manufacturer; Michael and Irene Ash(Eds.); Gower Publishing Ltd.; Aldershot, Hampshire, England, 1995.

“Intervention site” as used herein refers to the location in the bodywhere the coating is intended to be delivered (by transfer from, freeingfrom, and/or dissociating from the substrate). The intervention site canbe any substance in the medium surrounding the device, e.g., tissue,cartilage, a body fluid, etc. The intervention site can be the same asthe treatment site, i.e., the substance to which the coating isdelivered is the same tissue that requires treatment. Alternatively, theintervention site can be separate from the treatment site, requiringsubsequent diffusion or transport of the pharmaceutical or other agentaway from the intervention site.

“Compressed fluid” as used herein refers to a fluid of appreciabledensity (e.g., >0.2 g/cc) that is a gas at standard temperature andpressure. “Supercritical fluid,” “near-critical fluid,”“near-supercritical fluid,” “critical fluid,” “densified fluid,” or“densified gas,” as used herein refers to a compressed fluid underconditions wherein the temperature is at least 80% of the criticaltemperature of the fluid and the pressure is at least 50% of thecritical pressure of the fluid, and/or a density of +50% of the criticaldensity of the fluid.

Examples of substances that demonstrate supercritical or near criticalbehavior suitable for the present invention include, but are not limitedto carbon dioxide, isobutylene, ammonia, water, methanol, ethanol,ethane, propane, butane, pentane, dimethyl ether, xenon, sulfurhexafluoride, halogenated and partially halogenated materials such aschlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons,perfluorocarbons (such as perfluoromethane and perfuoropropane,chloroform, trichloro-fluoromethane, dichloro-difluoromethane,dichloro-tetrafluoroethane) and mixtures thereof. Preferably, thesupercritical fluid is hexafluoropropane (FC-236EA), or1,1,1,2,3,3-hexafluoropropane. Preferably, the supercritical fluid ishexafluoropropane (FC-236EA), or 1,1,1,2,3,3-hexafluoropropane for usein PLGA polymer coatings.

“Sintering” as used herein refers to the process by which parts of thepolymer or the entire polymer becomes continuous (e.g., formation of acontinuous polymer film). As discussed herein, the sintering process iscontrolled to produce a fully conformal continuous polymer (completesintering) or to produce regions or domains of continuous coating whileproducing voids (discontinuities) in the polymer. As well, the sinteringprocess is controlled such that some phase separation is obtained ormaintained between polymer different polymers (e.g., polymers A and B)and/or to produce phase separation between discrete polymer particles.Through the sintering process, the adhesions properties of the coatingare improved to reduce flaking of detachment of the coating from thesubstrate during manipulation in use. As described herein, in someembodiments, the sintering process is controlled to provide incompletesintering of the polymer. In embodiments involving incomplete sintering,a polymer is formed with continuous domains, and voids, gaps, cavities,pores, channels or, interstices that provide space for sequestering atherapeutic agent which is released under controlled conditions.Depending on the nature of the polymer, the size of polymer particlesand/or other polymer properties, a compressed gas, a densified gas, anear critical fluid or a super-critical fluid may be employed. In oneexample, carbon dioxide is used to treat a substrate that has beencoated with a polymer and a drug, using dry powder and RESSelectrostatic coating processes. In another example, isobutylene isemployed in the sintering process. In other examples a mixture of carbondioxide and isobutylene is employed. In another example,1,1,2,3,3-hexafluoropropane is employed in the sintering process.

When an amorphous material is heated to a temperature above its glasstransition temperature, or when a crystalline material is heated to atemperature above a phase transition temperature, the moleculescomprising the material are more mobile, which in turn means that theyare more active and thus more prone to reactions such as oxidation.However, when an amorphous material is maintained at a temperature belowits glass transition temperature, its molecules are substantiallyimmobilized and thus less prone to reactions. Likewise, when acrystalline material is maintained at a temperature below its phasetransition temperature, its molecules are substantially immobilized andthus less prone to reactions. Accordingly, processing drug components atmild conditions, such as the deposition and sintering conditionsdescribed herein, minimizes cross-reactions and degradation of the drugcomponent. One type of reaction that is minimized by the processes ofthe invention relates to the ability to avoid conventional solventswhich in turn minimizes-oxidation of drug, whether in amorphous,semi-crystalline, or crystalline form, by reducing exposure thereof tofree radicals, residual solvents, protic materials, polar-proticmaterials, oxidation initiators, and autoxidation initiators.

“Rapid Expansion of Supercritical Solutions” or “RESS” as used hereininvolves the dissolution of a polymer into a compressed fluid, typicallya supercritical fluid, followed by rapid expansion into a chamber atlower pressure, typically near atmospheric conditions. The rapidexpansion of the supercritical fluid solution through a small opening,with its accompanying decrease in density, reduces the dissolutioncapacity of the fluid and results in the nucleation and growth ofpolymer particles. The atmosphere of the chamber is maintained in anelectrically neutral state by maintaining an isolating “cloud” of gas inthe chamber. Carbon dioxide, nitrogen, argon, helium, or otherappropriate gas is employed to prevent electrical charge is transferredfrom the substrate to the surrounding environment.

“Electrostatic Rapid Expansion of Supercritical Solutions” or “e-RESS”or “eRESS” as used herein refers to Electrostatic Capture as describedherein combined with Rapid Expansion of Supercritical Solutions asdescribed herein. In some embodiments, Electrostatic Rapid Expansion ofSupercritical Solutions refers to Electrostatic capture as described inthe art, e.g., in U.S. Pat. No. 6,756,084, “Electrostatic deposition ofparticles generated from rapid expansion of supercritical fluidsolutions,” incorporated herein by reference in its entirety.

“Solution Enhanced Dispersion of Supercritical Solutions” or “SEDS” asused herein involves a spray process for the generation of polymerparticles, which are formed when a compressed fluid (e.g. supercriticalfluid, preferably supercritical CO₂) is used as a diluent to a vehiclein which a polymer is dissolved (one that can dissolve both the polymerand the compressed fluid). The mixing of the compressed fluid diluentwith the polymer-containing solution may be achieved by encounter of afirst stream containing the polymer solution and a second streamcontaining the diluent compressed fluid, for example, within one spraynozzle or by the use of multiple spray nozzles. The solvent in thepolymer solution may be one compound or a mixture of two or moreingredients and may be or comprise an alcohol (including diols, triols,etc.), ether, amine, ketone, carbonate, or alkanes, or hydrocarbon(aliphatic or aromatic) or may be a mixture of compounds, such asmixtures of alkanes, or mixtures of one or more alkanes in combinationwith additional compounds such as one or more alcohols, (e.g., from 0 or0.1 to 5% of a Ci to Ci₅ alcohol, including diols, triols, etc.). Seefor example U.S. Pat. No. 6,669,785, incorporated herein by reference inits entirety. The solvent may optionally contain a surfactant, as alsodescribed in, e.g., U.S. Pat. No. 6,669,785.

In one embodiment of the SEDS process, a first stream of fluidcomprising a polymer dissolved in a common solvent is co-sprayed with asecond stream of compressed fluid. Polymer particles are produced as thesecond stream acts as a diluent that weakens the solvent in the polymersolution of the first stream. The now combined streams of fluid, alongwith the polymer particles, flow out of the nozzle assembly into acollection vessel. Control of particle size, particle size distribution,and morphology is achieved by tailoring the following process variables:temperature, pressure, solvent composition of the first stream,flow-rate of the first stream, flow-rate of the second stream,composition of the second stream (where soluble additives may be addedto the compressed gas), and conditions of the capture vessel. Typicallythe capture vessel contains a fluid phase that is at least five to tentimes (5-1O×) atmospheric pressure.

“Electrostatic Dry Powder Coating” or “e-DPC” or “eDPC” as used hereinrefers to Electrostatic Capture as described herein combined with DryPowder Coating. e-DPC deposits material (including, for example, polymeror impermeable dispersed solid) on the device or other substrate as drypowder, using electrostatic capture to attract the powder particles tothe substrate. Dry powder spraying (“Dry Powder Coating” or “DPC”) iswell known in the art, and dry powder spraying coupled withelectrostatic capture has been described, for example in U.S. Pat. Nos.5,470,603, 6,319,541, and 6,372,246, all incorporated herein byreference in their entirety. Methods for depositing coatings aredescribed, e.g., in WO 2008/148013, “Polymer Films for Medical DeviceCoating,” incorporated herein by reference in its entirety.

“Dipping Process” and “Spraying Process” as used herein refer to methodsof coating substrates that have been described at length in the art.These processes can be used for coating medical devices withpharmaceutical agents. Spray coating, described in, e.g., U.S. Pat. No.7,419,696, “Medical devices for delivering a therapeutic agent andmethod of preparation” and elsewhere herein, can involve spraying orairbrushing a thin layer of solubilized coating or dry powder coatingonto a substrate. Dip coating involves, e.g., dipping a substrate in aliquid, and then removing and drying it. Dip coating is described in,e.g., U.S. Pat. No. 5,837,313 “Drug release stent coating process,”incorporated herein by reference in its entirety.

“Bulk properties” properties of a coating including a pharmaceutical ora biological agent that can be enhanced through the methods of theinvention include for example: adhesion, smoothness, conformality,thickness, and compositional mixing.

“Electrostatically charged” or “electrical potential” or “electrostaticcapture” as used herein refers to the collection of the spray-producedparticles upon a substrate that has a different electrostatic potentialthan the sprayed particles. Thus, the substrate is at an attractiveelectronic potential with respect to the particles exiting, whichresults in the capture of the particles upon the substrate. i.e. thesubstrate and particles are oppositely charged, and the particlestransport through the gaseous medium of the capture vessel onto thesurface of the substrate is enhanced via electrostatic attraction. Thismay be achieved by charging the particles and grounding the substrate orconversely charging the substrate and grounding the particles, bycharging the particles at one potential (e.g. negative charge) andcharging the substrate at an opposited potential (e.g. positive charge),or by some other process, which would be easily envisaged by one ofskill in the art of electrostatic capture.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without electrically charging the substrate” as used hereinrefers to any of these processes as performed without intentionallyelectrically charging the substrate. It is understood that the substratemight become electrically charged unintentially during any of theseprocesses.

“Depositing the active agent by an e-RESS, an e-SEDS, or an e-DPCprocess without creating an electrical potential between the substrateand a coating apparatus” as used herein refers to any of these processesas performed without intentionally generating an electrical potentialbetween the substrate and the coating apparatus. It is understood thatelectrical potential between the substrate and the coating apparatusmight be generated unintentially during any of these processes.

“Intimate mixture” as used herein, refers to two or more materials,compounds, or substances that are uniformly distributed or dispersedtogether.

“Layer” as used herein refers to a material covering a surface orforming an overlying part or segment. Two different layers may haveoverlapping portions whereby material from one layer may be in contactwith material from another layer. Contact between materials of differentlayers can be measured by determining a distance between the materials.For example, Raman spectroscopy may be employed in identifying materialsfrom two layers present in close proximity to each other.

While layers defined by uniform thickness and/or regular shape arecontemplated herein, several embodiments described herein relate tolayers having varying thickness and/or irregular shape. Material of onelayer may extend into the space largely occupied by material of anotherlayer. For example, in a coating having three layers formed in sequenceas a first polymer layer, a pharmaceutical agent layer and a secondpolymer layer, material from the second polymer layer which is depositedlast in this sequence may extend into the space largely occupied bymaterial of the pharmaceutical agent layer whereby material from thesecond polymer layer may have contact with material from thepharmaceutical layer. It is also contemplated that material from thesecond polymer layer may extend through the entire layer largelyoccupied by pharmaceutical agent and contact material from the firstpolymer layer.

It should be noted however that contact between material from the secondpolymer layer (or the first polymer layer) and material from thepharmaceutical agent layer (e.g.; a pharmaceutical agent crystalparticle or a portion thereof) does not necessarily imply formation of amixture between the material from the first or second polymer layers andmaterial from the pharmaceutical agent layer. In some embodiments, alayer may be defined by the physical three-dimensional space occupied bycrystalline particles of a pharmaceutical agent (and/or biologicalagent). It is contemplated that such layer may or may not be continuousas physical space occupied by the crystal particles of pharmaceuticalagents may be interrupted, for example, by polymer material from anadjacent polymer layer. An adjacent polymer layer may be a layer that isin physical proximity to be pharmaceutical agent particles in thepharmaceutical agent layer. Similarly, an adjacent layer may be thelayer formed in a process step right before or right after the processstep in which pharmaceutical agent particles are deposited to form thepharmaceutical agent layer.

As described herein, material deposition and layer formation providedherein are advantageous in that the pharmaceutical agent remains largelyin crystalline form during the entire process. While the polymerparticles and the pharmaceutical agent particles may be in contact, thelayer formation process is controlled to avoid formation of a mixturebetween the pharmaceutical agent particles the polymer particles duringformation of a coated device.

In some embodiments, the coating comprises a plurality of layersdeposited on said substrate, wherein at least one of the layerscomprises the active agent. In some embodiments, at least one of thelayers comprises a polymer. In some embodiments, the polymer isbioabsorbable. In some embodiments, the active agent and the polymer arein the same layer, in separate layers, or form overlapping layers. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active agent layer, a secondpolymer layer, a second active agent layer and a third polymer layer.

In some embodiments of the methods and/or devices provided herein, thecoating comprises a plurality of layers deposited on said substrate,wherein at least one of the layers comprises the active agent. In someembodiments, at least one of the layers comprises a polymer. In someembodiments, the polymer is bioabsorbable. In some embodiments, theactive agent and the polymer are in the same layer, in separate layers,or form overlapping layers. In some embodiments, the coating comprises aplurality of layers deposited on said substrate, wherein at least one ofthe layers comprises the pharmaceutical agent. In some embodiments, thepharmaceutical agent and the polymer are in the same layer, in separatelayers, or form overlapping layers. In some embodiments, the pluralityof layers comprise five layers deposited as follows: a first polymerlayer, a first active agent layer, a second polymer layer, a secondactive agent layer and a third polymer layer. In some embodiments, theplurality of layers comprise five layers deposited as follows: a firstpolymer layer, a first pharmaceutical agent layer, a second polymerlayer, a second pharmaceutical agent layer and a third polymer layer. Insome embodiments, the plurality of layers comprise five layers depositedas follows: a first polymer layer, a first active biological agentlayer, a second polymer layer, a second active biological agent layerand a third polymer layer.

In some embodiments, the device provides the coating to the interventionsite over an area of delivery greater than the outer surface contactarea of the substrate. In some embodiments, the area of delivery is atleast 110% greater than the outer surface contact area of the substrate.In some embodiments, the area of delivery is at least 110% to 200%greater than the outer surface contact area of the substrate. In someembodiments, the area of delivery is at least 200% greater than theouter surface contact area of the substrate.

“Laminate coating” as used herein refers to a coating made up of two ormore layers of material. Means for creating a laminate coating asdescribed herein (e.g.; a laminate coating comprising bioabsorbablepolymer(s) and pharmaceutical agent) may include coating the stent withdrug and polymer as described herein (e-RESS, e-DPC, compressed-gassintering). The process comprises performing multiple and sequentialcoating steps (with sintering steps for polymer materials) whereindifferent materials may be deposited in each step, thus creating alaminated structure with a multitude of layers (at least 2 layers)including polymer layers and pharmaceutical agent layers to build thefinal device (e.g.; laminate coated stent).

“Portion of the coating” and “portion of the active agent” as usedherein refer to an amount or percentage of the coating or active agentthat is freed, dissociated, and/or transferred from the substrate to theintervention site, either at a designated point in delivery, during acertain period of delivery, or in total throughout the entire deliveryprocess. In embodiments, the device and methods of the invention areadapted to free, dissociate, and/or transfer a certain amount of thecoating and/or active agent.

For example, in embodiments, at least about 10%, at least about 20%, atleast about 30%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating is adapted to be freed, dissociated, and/or to betransferred from the substrate to the intervention site. In embodiments,at least about 10%, at least about 20%, at least about 30%, at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, and/or at least about 99% of the active agent isadapted to be freed, dissociated, and/or to be transferred from thesubstrate to the intervention site.

The portion of the coating and/or that is freed, dissociated, ortransferred from the device substrate is influenced by any or acombination of, e.g., the size, shape, and flexibility of the devicesubstrate, the size, shape, surface qualities of and conditions (e.g.,blood or lymph circulation, temperature, etc.) at the intervention site,the composition of the coating, including the particular active agent(s)and specific polymer component(s) used in the coating, the relativeproportions of these components, the use of any release agent(s), andsubstrate characteristics. Any one or more of these and other aspects ofthe device and methods of the invention can be adapted to influence theportion of the coating and/or active agent freed, dissociated, and/ortransferred, as desired to produce the desired clinical outcome.

“Substantially all of the coating” as used herein refers to at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, at least about 97%, and/or at least about 99%percent of the coating that was present on the device prior to use.

“At least a portion of the substrate” as used herein refers to an amountand/or percentage of the substrate. In embodiments of the device andmethods of the invention wherein a coating is on “at least a portion ofthe substrate,” at least about 10%, at least about 20%, at least about30%, at least about 50%, at least about 75%, at least about 85%, atleast about 90%, at least about 95%, and/or at least about 99% of thesubstrate is coated. In embodiments wherein “at least a portion of thesubstrate” is bioabsorbable, at least about 10%, at least about 20%, atleast about 30%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the substrate is bioabsorbable.

“Transferring at least a portion” as used herein in the context oftransferring a coating or active agent from the substrate to anintervention site refers to an amount and/or percentage of the coatingor active agent that is transferred from the substrate to anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating or active agent istransferred from the substrate to an intervention site, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating or active agent istransferred from the substrate to the intervention site. In someembodiments, at least about 10%, at least about 20%, at least about 30%,at least about 50%, at least about 75%, at least about 85%, at leastabout 90%, at least about 95%, and/or at least about 99% of the coatingis adapted to transfer from the substrate to the intervention site. Insome embodiments, at least about 10% of the coating is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 20% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 30% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 50% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 75% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 85% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 90% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 95% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 99% of the coating is adaptedto transfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating transferred, or as a variation of thepercentage of the coating transferred).

In some embodiments, the coating portion that is adapted to transferupon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, device is adapted to transferless than about 1%, less than about 5%, less than about 10%. less thanabout 15%, less than about 25%, less than about 50%, less than about70%, less than about 80%, and/or less than about 90% of the coatingabsent stimulation of the coating.

In some embodiments, at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of theactive agent is adapted to transfer from the substrate to theintervention site. In some embodiments, at least about 10% of the activeagent is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 20% of the active agent isadapted to transfer from the substrate to the intervention site. In someembodiments, at least about 30% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 50% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 75% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 85% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 90% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 95% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 99% of the active agent is adapted totransfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the active agent canmean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as apercent of the percentage of the active agent transferred, or as avariation of the percentage of the active agent transferred).

In some embodiments, the active agent portion that is adapted totransfer upon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, the device is adapted totransfer less than about 1%, less than about 5%, less than about 10%.less than about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, and/or less than about 90% of the activeagent absent stimulation of the coating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 10% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 20% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 30% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 50% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 75% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 85% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 90% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 95% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 99% of the coating from the substrate to theintervention site. As used herein, “about” when used in reference to apercentage of the coating can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of thecoating transferred, or as a variation of the percentage of the coatingtransferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 10% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 20% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 30% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 50% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 75% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 85% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 90% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 95% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 99% of the active agent from the substrate tothe intervention site. As used herein, “about” when used in reference toa percentage of the active agent can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of the activeagent transferred, or as a variation of the percentage of the activeagent transferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, the stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%, lessthan about 90% of the active agent absent stimulation of the coating.

“Freeing at least a portion” as used herein in the context of freeing acoating and/or active agent from the substrate at an intervention siterefers to an amount and/or percentage of a coating or active agent thatis freed from the substrate at an intervention site. In embodiments ofthe device and methods of the invention wherein at least a portion of acoating or active agent is freed from the substrate at an interventionsite, at least about 10%, at least about 20%, at least about 30%, atleast about 50%, at least about 75%, at least about 85%, at least about90%, at least about 95%, and/or at least about 99% of the coating oractive agent is freed from the substrate at the intervention site. Insome embodiments, the device is adapted to free at least about 10%, atleast about 20%, at least about 30%, at least about 50%, at least about75%, at least about 85%, at least about 90%, at least about 95%, and/orat least about 99% of the coating from the substrate. In someembodiments, the device is adapted to free at least about 10% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 20% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 30% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 50% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 75% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 90% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 95% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating freed, or as a variation of thepercentage of the coating freed).

In some embodiments, the coating portion that frees upon stimulation ison at least one of a distal surface of the substrate, a middle surfaceof the substrate, a proximal surface of the substrate, and an abluminalsurface of the substrate.

In some embodiments, the stimulation decreases the contact between thecoating and the substrate. In some embodiments, the device is adapted tofree less than about 1%, less than about 5%, less than about 10%. lessthan about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, less than about 90% of the coatingabsent stimulation of the coating.

“Dissociating at least a portion” as used herein in the context ofdissociating a coating and/or active agent from the substrate at anintervention site refers to an amount and/or percentage of a coatingand/or active agent that is dissociated from the substrate at anintervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdissociated from the substrate at an intervention site, at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating and/or active agent isdissociated from the substrate at the intervention site.

In some embodiments, the device is adapted to dissociate at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate. Insome embodiments, the device is adapted to dissociate at least about 10%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 20% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 30% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 50% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 75% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 85% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 90% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 95% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 99% ofthe coating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating dissociated, or as a variation of thepercentage of the coating dissociated).

In some embodiments, the coating portion that dissociates uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments,stimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to dissociate less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

“Depositing at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is deposited atan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdeposited at an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is deposited at theintervention site. In some embodiments, stimulating decreases thecontact between the coating and the substrate. In some embodiments,depositing deposits less than about 1%, less than about 5%, less thanabout 10%. less than about 15%, less than about 25%, less than about50%, less than about 70%, less than about 80%, and/or less than about90% of the coating absent stimulating at least one of the coating andthe substrate.

“Delivering at least a portion” as used herein in the context of acoating and/or active agent at an intervention site refers to an amountand/or percentage of a coating and/or active agent that is delivered toan intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent isdelivered to an intervention site, at least about 10%, at least about20%, at least about 30%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating and/or active agent is delivered to theintervention site.

In some embodiments, the device is adapted to deliver at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating to the intervention site.In some embodiments, the device is adapted to deliver at least about 10%of the coating to the intervention site. In some embodiments, the deviceis adapted to deliver at least about 20% of the coating to theintervention site. In some embodiments, the device is adapted to deliverat least about 30% of the coating to the intervention site. In someembodiments, the device is adapted to deliver at least about 50% of thecoating to the intervention site. In some embodiments, the device isadapted to deliver at least about 75% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver at leastabout 85% of the coating to the intervention site. In some embodiments,the device is adapted to deliver at least about 90% of the coating tothe intervention site. In some embodiments, the device is adapted todeliver at least about 95% of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 99% ofthe coating to the intervention site. As used herein, “about” when usedin reference to a percentage of the coating can mean ranges of 1%-5%, of5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentage ofthe coating delivered, or as a variation of the percentage of thecoating delivered).

In some embodiments, the coating portion that is delivered uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments, thestimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to deliver less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, depositing at least a portion of the coatingcomprises depositing at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of thecoating at the intervention site. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, depositing deposits less than about 1%, less than about 5%,less than about 10%. less than about 15%, less than about 25%, less thanabout 50%, less than about 70%, less than about 80%, and/or less thanabout 90% of the coating absent stimulating at least one of the coatingand the substrate.

“Tacking at least a portion” as used herein in the context of tacking atleast a portion of the coating to an intervention site refers to anamount and/or percentage of a coating and/or active agent that is tackedat an intervention site. In embodiments of the device and methods of theinvention wherein at least a portion of a coating and/or active agent istacked at an intervention site, at least about 10%, at least about 20%,at least about 30%, at least about 50%, at least about 75%, at leastabout 85%, at least about 90%, at least about 95%, and/or at least about99% of the coating and/or active agent is tacked at the interventionsite. In some embodiments, stimulating decreases the contact between thecoating and the substrate. In some embodiments, tacking tacks less thanabout 1%, less than about 5%, less than about 10%. less than about 15%,less than about 25%, less than about 50%, less than about 70%, less thanabout 80%, and/or less than about 90% of the coating absent stimulatingat least one of the coating and the substrate. In some embodiments, thedevice comprises a tacking element that cooperates with the stimulationto tack the coating to the intervention site. In some embodiments, thedevice comprises a tacking element that tacks the coating to thesubstrate until stimulating with a stimulation.

“Adhere,” “adherence,” “adhered,” “cohere,” “coherence,” “cohered,” andrelated terms, as used herein in the context of adherence or coherenceof the substrate to the coating refer to an interaction between thesubstrate and the coating that is sufficiently strong to maintain theassociation of the coating with the substrate for an amount of timeprior to the stimulation, e.g., mechanical, chemical, thermal,electromagnetic, or sonic stimulation, that is intended to cause thecoating to be freed, dissociated, and/or transferred. These same terms,as used in the context of an interaction between the coating and thetarget tissue area and/or intervention site refer to an interactionbetween the coating and the target tissue area and/or intervention sitethat is sufficient to keep the coating associated with the target tissuearea and/or intervention site for an amount of time as desired fortreatment, e.g., at least about 12 hours, about 1 day, about 3 days,about 5 days, about 7 days, about 14 days, about 3 weeks, about 4 weeks,about 45 days, about 60 days, about 90 days, about 180 days, about 6months, about 9 months, about 1 year, about 1 to about 2 days, about 1to about 5 days, about 1 to about 2 weeks, about 2 to about 4 weeks,about 45 to about 60 days, about 45 to about 90 days, about 30 to about90 days, about 60 to about 90 days, about 90 to about 180 days, about 60to about 180 days, about 180 to about 365 days, about 6 months to about9 months, about 9 months to about 12 months, about 9 months to about 15months, and about 1 year to about 2 years.

“Balloon” as used herein refers to a flexible sac that can be inflatedwithin a natural or non-natural body lumen or cavity, or used to createa cavity, or used to enlarge an existing cavity. The balloon can be usedtransiently to dilate a lumen or cavity and thereafter may be deflatedand/or removed from the subject during the medical procedure orthereafter. In embodiments, the balloon can be expanded within the bodyand has a coating thereon that is freed (at least in part) from theballoon and left behind in the lumen or cavity when the balloon isremoved. A coating can be applied to a balloon either after the balloonhas been compacted for insertion, resulting in a coating that partiallycovers the surface of the balloon, or it can be applied prior to orduring compaction. In embodiments, a coating is applied to the balloonboth prior to and after compaction of the balloon. In embodiments, theballoon is compacted by, e.g., crimping or folding. Methods ofcompacting balloons have been described, e.g., in U.S. Pat. No.7,308,748, “Method for compressing an intraluminal device,” and U.S.Pat. No. 7,152,452, “Assembly for crimping an intraluminal device andmethod of use,” relating to uniformly crimping a balloon onto a catheteror other intraluminal device, and U.S. Pat. No. 5,350,361 “Tri-foldballoon for dilatation catheter and related method,” relating to balloonfolding methods and devices, all incorporated herein by reference intheir entirety. In some embodiments the balloon is delivered to theintervention site by a delivery device. In some embodiments, thedelivery device comprises catheter. In some embodiments, the balloon isan angioplasty balloon. Balloons can be delivered, removed, andvisualized during delivery and removal by methods known in the art,e.g., for inserting angioplasty balloons, stents, and other medicaldevices. Methods for visualizing a treatment area and planninginstrument insertion are described, e.g., in U.S. Pat. No. 7,171,255,“Virtual reality 3D visualization for surgical procedures” and U.S. Pat.No. 6,610,013, “3D ultrasound-guided intraoperative prostatebrachytherapy,” incorporated herein by reference in their entirety.

“Compliant balloon” as used herein refers to a balloon which conforms tothe intervention site relatively more than a semi-compliant balloon andstill more so than a non-compliant balloon. Compliant balloons expandand stretch with increasing pressure within the balloon, and are madefrom such materials as polyethylene or polyolefin copolymers. There isin the art a general classification of balloons based on theirexpandability or “compliance” relative to each other, as described e.g.,in U.S. Pat. No. 5,556,383, “Block copolymer elastomer catheterballoons.” Generally, “non-compliant” balloons are the least elastic,increasing in diameter about 2-7%, typically about 5%, as the balloon ispressurized from an inflation pressure of about 6 atm to a pressure ofabout 12 atm, that is, they have a “distension” over that pressure rangeof about 5%. “Semi-compliant” balloons have somewhat greaterdistensions, generally 7-16% and typically 10-12% over the samepressurization range. “Compliant” balloons are still more distensible,having distensions generally in the range of 16-40% and typically about21% over the same pressure range. Maximum distensions, i.e. distensionfrom nominal diameter to burst, of various balloon materials may besignificantly higher than the distension percentages discussed abovebecause wall strengths, and thus burst pressures, vary widely betweenballoon materials. These distension ranges are intended to providegeneral guidance, as one of skill in the art will be aware that thecompliance of a balloon is dependent on the dimensions and/orcharacteristics of the cavity and/or lumen walls, not only theexpandability of the balloon.

A compliant balloon may be used in the vasculature of a subject. Acompliant balloon might also be used in any tube or hole outside thevasculature (whether naturally occurring or man-made, or created duringan injury). For a non-limiting example, a compliant balloon might beused in a lumpectomy to put a coating at the site where a tumor wasremoved, to: treat an abscess, treat an infection, prevent an infection,aid healing, promote healing, or for a combination of any of thesepurposes. The coating in this embodiment may comprise a growth factor.

“Non-Compliant balloon” as used herein refers to a balloon that does notconform to the intervention site, but rather, tends to cause theintervention site to conform to the balloon shape. Non-compliantballoons, commonly made from such materials as polyethyleneterephthalate (PET) or polyamides, remain at a preselected diameter asthe internal balloon pressure increases beyond that required to fullyinflate the balloon. Non-compliant balloons are often used to dilatespaces, e.g., vascular lumens. As noted with respect to a compliantballoon, one of skill in the art will be aware that the compliance of aballoon is dependent on the dimensions and/or characteristics of thecavity and/or lumen walls, not only the expandability of the balloon.

“Cutting balloon” as used herein refers to a balloon commonly used inangioplasty having a special balloon tip with cutting elements, e.g.,small blades, wires, etc. The cutting elements can be activated when theballoon is inflated. In angioplasty procedures, small blades can be usedscore the plaque and the balloon used to compress the fatty matteragainst the vessel wall. A cutting balloon might have tacks or otherwire elements which in some embodiments aid in freeing the coating fromthe balloon, and in some embodiments, may promote adherence or partialadherence of the coating to the target tissue area, or some combinationthereof. In some embodiments, the cutting balloon cutting elements alsoscore the target tissue to promote the coating's introduction into thetarget tissue. In some embodiments, the cutting elements do not cuttissue at the intervention site. In some embodiments, the cuttingballoon comprises tacking elements as the cutting elements.

“Inflation pressure” as used herein refers to the pressure at which aballoon is inflated. As used herein the nominal inflation pressurerefers to the pressure at which a balloon is inflated in order toachieve a particular balloon dimension, usually a diameter of theballoon as designed. The “rated burst pressure” or “RBP” as used hereinrefers to the maximum statistically guaranteed pressure to which aballoon can be inflated without failing. For PTCA and PTA catheters, therated burst pressure is based on the results of in vitro testing ot thePTCA and/or PTA catheters, and normally means that at least 99.9% of theballoons tested (with 95% confidence) will not burst at or below thispressure.

“Tacking element” as used herein refers to an element on the substratesurface that is used to influence transfer of the coating to theintervention site. For example, the tacking element can comprise aprojection, e.g., a bump or a spike, on the surface of the substrate. Inembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, tacking element can comprise a wire, and the wire can beshaped in the form of an outward pointing wedge. In certain embodiments,the tacking element does not cut tissue at the intervention site.

As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to:As used herein, a “surgical tool” refers to any tool used in a surgicalprocedure. Examples of surgical tools include, but are not limited to: aknife, a scalpel, a guidewire, a guiding catheter, a introductioncatheter, a distracter, a needle, a syringe, a biopsy device, anarticulator, a Galotti articulator, a bone chisel, a bone crusher, acottle cartilage crusher, a bone cutter, a bone distractor, an Ilizarovapparatus, an intramedullary kinetic bone distractor, a bone drill, abone extender, a bone file, a bone lever, a bone mallet, a bone rasp, abone saw, a bone skid, a bone splint, a bone button, a caliper, acannula, a catheter, a cautery, a clamp, a coagulator, a curette, adepressor, a dilator, a dissecting knife, a distractor, a dermatome,forceps, dissecting forceps, tissue forceps, sponge forceps, boneforceps, Carmalt forceps, Cushing forceps, Dandy forceps, DeBakeyforceps, Doyen intestinal forceps, epilation forceps, Halstead forceps,Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, a hook, anerve hook, an obstetrical hook, a skin hook, a hypodermic needle, alancet, a luxator, a lythotome, a lythotript, a mallet, a partschmallet, a mouth prop, a mouth gag, a mammotome, a needle holder, anoccluder, an osteotome, an Epker osteotome, a periosteal elevator, aJoseph elevator, a Molt periosteal elevator, an Obweg periostealelevator, a septum elevator, a Tessier periosteal elevator, a probe, aretractor, a Senn retractor, a Gelpi retractor, a Weitlaner retractor, aUSA-Army/Navy retractor, an O'Connor-O'Sullivan retractor, a Deaverretractor, a Bookwalter retractor, a Sweetheart retractor, a Joseph skinhook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rakeretractor, a flexible rake retractor, a Ragnell retractor, aLinde-Ragnell retractor, a Davis retractor, a Volkman retractor, aMathieu retractor, a Jackson tracheal hook, a Crile retractor, aMeyerding finger retractor, a Little retractor, a Love Nerve retractor,a Green retractor, a Goelet retractor, a Cushing vein retractor, aLangenbeck retractor, a Richardson retractor, a Richardson-Eastmannretractor, a Kelly retractor, a Parker retractor, a Parker-Mottretractor, a Roux retractor, a Mayo-Collins retractor, a Ribbonretractor, an Alm retractor, a self retaining retractor, a Weitlanerretractor, a Beckman-Weitlaner retractor, a Beckman-Eaton retractor, aBeckman retractor, an Adson retractor, a rib spreader, a rongeur, ascalpel, an ultrasonic scalpel, a laser scalpel, scissors, irisscissors, Kiene scissors, Metzenbaum scissors, Mayo scissors, Tenotomyscissors, a spatula, a speculum, a mouth speculum, a rectal speculum,Sim's vaginal speculum, Cusco's vaginal speculum, a sternal saw, asuction tube, a surgical elevator, a surgical hook, a surgical knife,surgical mesh, a surgical needle, a surgical snare, a surgical sponge, asurgical spoon, a surgical stapler, a suture, a syringe, a tonguedepressor, a tonsillotome, a tooth extractor, a towel clamp, towelforceps, Backhaus towel forceps, Lorna towel forceps, a tracheotome, atissue expander, a subcutaneus inflatable balloon expander, a trephine,a trocar, tweezers, and a venous cliping. In some embodiments, asurgical tool may also and/or alternatively be referred to as a tool forperforming a medical procedure. In some embodiments, a surgical tool mayalso and/or alternatively be a tool for delivering to the interventionsite a biomedical implant.

“Reproductive care” as used herein refers to care of a subject'sreproductive system. Active agents are contemplated for use inembodiments of methods and/or devices provided herein for Reproductivecare. Devices and methods provided herein are contemplated for use inReproductive care. The subject may be male or female, the care may bepreventative, or to treat a condition, ailment, or disease. As usedherein, the terms “condition” and “ailment” are interchangeable. Forexample, Reproductive care of a subject's reproductive system mayinclude, in some embodiments, hormone delivery to reproductive organs,whether for birth control or reproductive assistance or for anotherpurpose, fertility treatment, whether to reduce fertility or to increasefertility, infection treatment, such as treatment of yeast infections orother infections, and treatment and/or prevention of sexuallytransmitted diseases (STDs) such as bacterial vaginosis, chancroid,donovanosis, gonorrhea, lymphogranuloma venereum, chlamydia,non-gonococcal urethritis, staphylococcal infection, syphillis, tineacruris, adenovirus, viral hepatitus, herpes symplex, HIV/AIDS, HTLV 1,2,genital warts, human papillomavirus HPV, molluscum contagiosum,mononucleosis, kaposi's sarcoma (Herpes 8), and/or trichomoniasis. Inembodiments, the devices and methods of the invention are used to treatpelvic inflammatory disease (PID), including, e.g., infection and/orinflammation of the fallopian tube, ovary, endometrium, and other pelvicinfections. In embodiments, PID is treated by local delivery to thefallopian tubes and/or ovaries. In other embodiments, STDs such aschlamydia and gonorrhoea are treated via a similar administration route.A dosage of clindamycin for the systemic treatment of pelvicinflammatory disease is, e.g., 900 mg IV q8h (in combination withgentamicin) administered for 14 days. Treatment of PID is described by,e.g., Mollen, et al., 2006, “Prevalence of tubo-ovarian abcess inadolescents diagnosed with pelvic inflammatory disease in a pediatricemergency department,” Pediatr Emerg Care 22(9): 621-625; Hartmann, etal., 2009, “Tubo-ovarian abscess in virginal adolescents:exposure of theunderlying etiology,” J Pediatr Adolesc Gynecol 22(3):e13-16; Lehmann,et al., 2001, “Drug treatment of nonviral sexually transmitted diseases:specific issues in adolescents,” Paediatr Drugs 3(7):481-494.Reproductive organs include not only the gonads and/or ovaries, but anytissue in the reproductive system of a male or a female subject.

Intravaginal and transvaginal treatment of infections are alsocontemplated in certain embodiments of the methods and/or devices of theinvention. Formulations of drugs for these indications are described in,e.g., U.S. Pat. No. 6,416,779, “Device and method for intravaginal ortransvaginal treatment of fungal, bacterial, viral or parasiticinfections,” incorporated herein by reference in its entirety. Fungal,bacterial, viral and parasitic infections and conditions, can be treatedby methods comprising inserting into the vagina a device of theinvention coated with a drug formulated for treatment of theseconditions, with, e.g., a mucoadhesive agent to promote adherence of thedrug to the vaginal wall. The mucoadhesive agent can be a polymer suchas an alginate, pectin, or a cellulose derivative such as hydroxypropylmethylcellulose. Mucoadhesive formulations are described, e.g., byEdsman, et al., 2005, “Pharmaceutical applications of mucoadhesion forthe non-oral routes,’ J. Pharm. Pharmacol. 57(1):3-22. The drug may betherapeutically active topically by acting directly on vaginalepithelium or mucosa or it may be transported transvaginally into theuterus, cervix and even into the general circulation. U.S. Pat. No.6,416,779 describes dosages of agents for intravaginal and transvaginalformulations for treating various diseases, e.g., as follows: ingeneral, the dosage comprises from about 10 to about 2000 mg of theantibiotic per daily dose to be delivered transvaginally to the cervix.The transvaginal formulation can comprise a penetration enhancer and/orsorption promoter and/or mucoadhesive agent. The antibiotic dose dependson the antibiotic anti-infective activity. For treatment of chlamydia,the dosage is typically within 100-2000 mg/day dose administered for atleast seven days, unless otherwise indicated. For transvaginal treatmentof gonorrhea, lumefloxacin (400 mg), norfloxacin (800 mg), afloxam (400mg), ciproflaxin (500 mg), azitromycin (1000 mg), cefltoxime (400 mg)and doxicycline (100 mg) twice a day/7 days can be administered in dosesas needed to alleviate the symptoms and to effectively eliminategonococcus from the individual organism in daily doses from about 400 mgto about 3000 mg. The formulation may, additionally, contain about500-1000 mg of probenecid. For local treatment of herpes simplex,antiviral drugs such as acyclovir (200-1200 mg/day) or famciclovir(100-1200 mg/day), are administered for at least 7 days in a combinationof transvaginal and intravaginal formulation. When using the devices andmethods of the present invention, it is understood that the amount ofagent transferred via a coating to an intervention site can be varieddepending on the rate of release of the active agent from the coatingafter transfer, to achieve dosages comparable to those used with otherlocal treatment methods.

Hormones that can be delivered locally using the devices and methods ofthe invention include, e.g.: delivery of 20 micrograms/day ethinylestradiol to hypoestrogenic subjects for peak bone mass acquisitionduring adolescence; 200 micrograms/day of 17β-estradiol to relievesevere post-menopausal symptoms; 400 micrograms/day of the GNRH agonistnafarelin for 4 weeks in the initial treatment of endometriosis,followed by half-dose therapy (200 micrograms/day) for 20 weeks; andestradiol release of 100 mg/day of estradiol, as its 3-acetate ester canmaintain a circulating plasma concentration of 300 pmol/L of the drug,to treat vaginal atrophy or for hormone replacement therapy (HRT). Ingeneral, estradiol can be administered intravaginally in a dosage amountof 25 about 10 to about 50 ug, preferably about 15 to about 40 g, forexample about 25 g, no more than once daily. A suitable dosage amount ofmethyltestosterone is likely to be found in the range of about 0.5 toabout 2.5 mg, no more than once daily, but greater or lesser amounts canbe safe and effective in particular cases. Other androgens can beadministered in dosage amounts therapeutically equivalent to thesedosage amounts of methyltestosterone. One of skill in the art willunderstand that amount of hormone (or any other active agent) that canbe transferred via a coating to an intervention site will vary dependingon the rate of release of the active agent from the coating aftertransfer. Locally administered therapies and dosages have been describedin, e.g., U.S. Pat. App. No. 2006/0287611, “Administration oftherapeutic or diagnostic agents using interlabial pad,” U.S. Pat. No.6,682,757, “Titratable dosage transdermal delivery system,” WO03/039553, “Compositions for treatment of postmenopausal female sexualdysfunction,” all incorporated by reference herein.

Pharmaceutical agents useful in these aspects of the invention areactive on the vaginal epithelium, mucosa or on the uterine epithelium orcervix. The pharmaceutical agent is preferably selected from the groupconsisting of antifungal, antiviral, antibacterial or antiparasiticagents. Examples of anti-fungal drugs suitable for use in this and otheruses of the invention include miconazole, terconazole, isoconazole,fenticonazole, fluconazole, ketoconazole, clotrimazole, butoconazole,econazole, metronidazole, clindamycin, and 5-fluoracil. Anti-viral drugsinclude acyclovir, AZT, famciclovir and valacyclovir. Antibacterialagents suitable for treatment of bacterial vaginosis are metronidazole,clindamycin, ampicillin, amoxicillin, tetracycline, doxycycline andother antibiotics. The anti-trichomonas agent suitable for treatment oftrichomoniasis caused by Trichomonas vaginalis is metronidazole.

“Urologic care” as used herein refers to treatment and prevention of anydisease or dysfunction of any part of the male and female urinary tractand/or the urinary system, and the male reproductive system. Activeagents are contemplated for use in embodiments of methods and/or devicesprovided herein for urologic care. Devices and methods provided hereinare contemplated for use in Urologic care. The urinary tract and/or theurinary system consists of the organs involved in the production andelimination of liquid waste (urine) from the body: the kidneys, ureters,bladder, and urethra. There are also two adrenal glands, one on top ofeach kidney, that produce important hormones the body needs, which iscontemplated to be part of the urinary tract and/or urinary system asused herein. The male reproductive organs include the prostate, penisand testes (testicles).

Urologic conditions and ailments include sexual dysfunction andfertility issues, as well as general urology issues. Conditions include,for example, urinary stones, urinary incontinence, cancers of theurologic tract (e.g., bladder cancer, kidney cancer, and cancer of theurethra), cancers of the male reproductive tracts (e.g., testicularcancer, prostate cancer), Benign Prostate Hyperplasia (BPH),hypogonadism (Decreased Testosterone), erectile dysfunction, prematureejaculation, Peyronie's Disease, prostatitis, seminal vesiculitis,prostatic abscess, bladder neck hypertrophy and adrenal tumors. Urologiccare also encompasses vasectomy and reversal of vasectomy.

BPH, including chronic prostatitis and chronic pelvic pain syndrome(CP/CPPS) is a common disorder affecting 50-80% of the aged malepopulation. The cause is attributed to either underlying infection orinflammation and treatment and therefore involves antibiotic therapysuch as fluoroquinolones or ciprofloxacin and anti-inflammatory therapywith alpha-adrenergic receptor antagonists such as alfuzosin. Thesedrugs are typically given systemically usually over the course of two tofour months. Localized infection and inflammation can be treated muchmore effectively if therapy is targeted to the infection site therebyallowing increased local concentrations and reduced systemic toxicities.

Using the device and methods of the invention to apply a drug-releasingcoating to the wall of the prostate, treatment agents can be deliveredfor an extended period (at least two months). Local delivery alsoreduces the risk of development of antibiotic resistance. Using abiodegradable coating matrix, repeat administration can be provided asneeded without concerns about build up of polymer.

Treatment of BPH and chonic prostatitis are described in the literature.See, e.g., Murphy, et al., 2009, “Chronic prostatitis: managementstrategies, Drugs 69(1): 71-84; Pontari, 2003, “Chronicprostatitis/chronic pelvic pain syndrome in elderly men: toward betterunderstanding and treatment,” Drugs Aging 20(15): 1111-1115; Mehik, etal., 2003, “Alfuzosin treatment for chronic prostatitis/chronic pelvicpain syndrome: a prospective, randomized, double-blind,placebo-controlled, pilot study,” Urology 62(3):425-429; Wagenlehner, etal., Jun. 3, 2009, “A pollen extract (Cernilton) in patients withinflammatory chronic prostatitis chronic pelvic pain syndrome: amulticentre, randomized, prospective, double-blind, placebo-controlledphase 3 study,” Eur Urol 9 (Epub); Fibbi, et al., Jun. 8, 2009, “Chronicinflammation in the pathogenesis of benign prostatic hyperplasia,” Int.J. Androl. (Epub).

Stress incontinence, urge incontinence, and pyelitis of pregnancy arecommon urological conditions in the female. The most important factor inthe production of urge incontinence is infection. Some pathologicalconditions which may be associated with urge incontinence areurethritis, cystitis, urethral stricture, bladder-neck obstruction,urethral diverticula, urethral caruncle and the urgency-frequencysyndrome. Therapy is directed toward the eradication of infection andtreatment of the specific lesion.

In embodiments, antiinflammatory or other agents are delivered, e.g., tothe posterior urethra, for treatment of the pain and inflammationassociated with prostatitis/chronic pelvic pain syndrome using thedevices and methods of the invention. In embodiments, prematureejaculation caused by inflammation is treated in this manner. (See,e.g., A Pontari, M., 2002, “Inflammation and anti-inflammatory therapyin chronic prostatis,” Urology 60(6Suppl):29-33, and Boneff, A., 1971,“Topical Treatment of Chronic Prostatitis and Premature Ejaculation,”International Urology and Nephrology 4(2): 183-186, describingintroduction of a hydrocortisone-antibiotic mixture into the posteriorurethra).

In embodiments, the devices and methods of the invention are useful forlocal delivery of agents including mitomycin C and BCG for treatment ofurinary tract transitional cell carcinoma (TCC). Transitional cellcarcinoma (TCC, also urothelial cell carcinoma or UCC) is a type ofcancer that typically occurs in the urinary system: the kidney, urinarybladder, and accessory organs. It is the most common type of bladdercancer and cancer of the ureter, urethra, and urachus, and it is thesecond most common type of kidney cancer. TCC arises from thetransitional epithelium, a tissue lining the inner surface of thesehollow organs. Bacillus Calmette-Guerin (BCG) therapy andCpG-Oligodeoxynucleotides (CpG-ODN), a synthetic agent, have been usedto prevent the recurrence of urinary tract transitional cell carcinoma(TCC). Both CpG-ODN and BCG likely work by stimulating a potentimmunological response. They are currently infused into the urinarytract through a catheter at weekly intervals under local anesthesia.This procedure is unpleasant, cumbersome and expensive. In embodiments,a single, topical application of the an appropriate agent (e.g., BCG,CpG-ODN, and/or mitomycin C) is applied directly to the wall of theurethra, particularly near the original lesion site, using, e.g., afoley-type catheter.

The use of a bioresorbable polymer with the pharmaceutical agent canincrease the concentration of the agent delivered to the target tissue,retaining it locally, thereby increasing effectiveness and reducingoverall bladder irritation. It can also reduce the threat of spread ofBCG to sexual partners. Use of a polymer that can provide for controlleddrug delivery over the course of 6-8 weeks can negate the need forrepeat application procedures.

Either alone or in combination with BCG therapy, the application ofmitomycin C can also reduce subsequent inflammation and promote healingafter endoscopic surgery. Local treatment of TCC using BCG, CpG-ODN,and/or mitomycin C is described in the literature, e.g., by: Thalmann,et al., 2002, “Long-term experience with bacillus Calmette-Guerintherapy of upper urinary tract transitional cell carcinoma in patientsnot eligible for surgery,” J Urol. 168(4 Pt 1): 1381-1385; Olbert, etal., 2009, “In vitro and in vivo effects of CpG-Oligodeoxynucleotides(CpG-ODN) on murine transitional cell carcinoma and on the native murineurinary bladder wall,” Anticancer Res. 29(6):2067-2076; Melonakos, etal., “Treatment of low-grade bulbar transitional cell carcinoma withurethral instillation of mitomycin C, Oct. 28, 2008, Adv Urol. 173694Epub; Di Stasi, et al., 2005, “Percutaneous sequential bacillusCalmette-Guerin and mitomycin C for panurothelial carcinomatosis,” Can JUrol 12(6):2895-2898.

In specific embodiments, the devices and methods of the invention areused for intravesical drug therapy of bladder cancer. In bladder cancer,cancer cells invade the wall of the bladder. The wall of the bladderconsists of several layers and the treatment modalities used to treatbladder cancer are typically selected on the basis of how far the cancerhas penetrated into the layers of the bladder wall.

The majority of superficial tumors (e.g., those that are confined to themucosa and lamina propria of the bladder) are treated by cystoscopicsurgery or in some cases intravesical drug therapy. In cases where thecarcinoma has penetrated the muscular wall of the bladder (i.e. wherethe cancer has progressed to invasive bladder cancer that invades thedeeper layers of the bladder wall, and possibly nearby organs, such asthe uterus, vagina, or prostate gland) metastatic disease is likely tooccur after surgery. Additional chemotherapy, either systemic or local,is thus needed. Response to treatment of bladder transitional cellcarcinoma appears to be related to drug concentration and duration ofexposure, therefore the capability of the devices and methods of theinvention to deliver a concentrated dose of agent directly to thetreatment site is advantageous for this indication.

Methods of treatment and agents used in treating bladder and urinarytract cancers are described in, e.g., U.S. Pat. No. 7,326,734,“Treatment of bladder and urinary tract cancers,” and U.S. Pat. No.6,355,691, “Urushiol therapy of transitional cell carcinoma of thebladder,” (describing intravesical administration of urushiol) bothincorporated herein by reference in their entirety.

A variety of agents have been reported to have significant activity intransitional cell carcinoma of the bladder, including cisplatin-basedregimens such as MVAC (methotrexate, vinblastine, doxorubicin, andcisplatin), which has become standard for patients with metastaticurothelial carcinoma. A drawback of MVAC is toxicity and poor patienttolerance. Local administration of MVAC using the devices and methods ofthe invention could allow lower dosages to be administered, resulting inbetter tolerance. Other agents useful for treating TCC of the bladderare paclitaxel and docetaxel, gemcitabine, thiotepa, valrubicin,epirubicin, interferon alpha 2b, ifosfamide, and the methotrexateanalogues, trimetrexate and piritrexim.

Bladder cancer is frequently treated by an initial instillation of drug,e.g., within 6 hours of tumor resection, followed by a 4-8 weekinduction treatment, followed by about one year or more of a maintenanceregimen. Intravesical combination chemotherapies for administration topatients having bladder cancer are described, e.g., by Witjes, et al.,2008 January, “Intravesical pharmacotherapy for non-muscle-invasivebladder cancer: a critical analysis of currently available drugs,treatment schedules, and long-term results,” Eur Urol. 53(1):45-52, andLamm, et al., Oct. 26, 2005, “Bladder Cancer: Current OptimalIntravesical Treatment: Pharmacologic Treatment,” Urologic Nursing25(5):323-6, 331-2.

Chemotherapy can be administered at or near the time of tumor resection,to prevent tumor recurrence. Immunotherapy (e.g., BCG), has been shownto reduce recurrence when given as maintenance therapy rather than atthe time of resection. In general, immunotherapy is seen as moreeffective against high-grade carcinoma, and chemotherapy as moreeffective against low-grade carcinoma.

Chemotherapy agent dosing: The standard intravesicular dosage ofthiotepa is 30 mg in 15 cc sterile water. When given as a singleinstillation at the time of tumor resection, an exposure of 30 minutesis used. When not given in conjunction with tumor resection, doses of 30mg to 60 mg are used in 15 cc to 30 cc of sterile water and held for 2hours. Treatment is given weekly for 4 to 8 weeks, depending on volumeof residual disease. When repeated treatments are used, blood countsshould be obtained, since thiotepa has a molecular weight of 188 anddrugs with molecular weight less than 300 are more readily absorbed fromthe bladder.

The standard dosage of mitomycin C is 40 mg in 20 cc sterile water.Mitomycin C should not be given if bladder perforation is suspected. Ina randomized study, recurrence was reportedly nearly cut in half byusing an optimized schedule: 40 mg/20 cc (compared with 20 mg/20 cc),overnight dehydration, ultrasound-confirmed complete bladder emptying,alkalinization using 1.3 g of sodium bicarbonate the night before,morning of, and 30 minutes prior to treatment. Mitomycin C isinactivated by acid urine (Au, et al. 2001, “Methods to improve efficacyof intravesical mitomycin C: Results of a randomized phase III trial”Journal of the National Cancer Institute, 93(8), 597-604). It has beenreported that that local hyperthermia, which can be obtained with amicrowave applicator inserted into the bladder with a special cathetercan enhance the efficacy of mitomycin C, albeit with a significantincrease in systemic absorption.

The standard dosage of doxorubicin is 50 mg in 25 cc of sterile water.Doxorubicin should not be given if bladder perforation is suspected.Optimal response occurs when given as a single instillation at the timeof tumor resection. An exposure of 30 minutes is used when given at thetime of surgery. When given to treat existing disease rather thanprevent recurrence, treatment is held for 2 hours, and given weekly for4 to 8 weeks, depending on volume of residual disease.

The standard dosage of epirubicin is 80 mg in 40 cc sterile water. Likedoxorubicin, mitomycin C, and valrubicin, epirubicin is a vesicant andwill result in necrosis with extravasation. Best results occur withimmediate postoperative instillation, but instillation should not bedone if bladder perforation or any risk for extravasation is present,since this would put the patient at risk for peritonitis.

Valrubicin was specifically approved for BCG-refractory carcinoma insitu of the bladder. The standard dose is 800 mg in 75 mL normal salineweekly for 6 weeks.

Immunotherapy agent dosing: Immunotherapies (also called adjuvanttherapies) include not only bacillus Calmette-Guerin (BCG), as describedabove, but also Interferon Alpha 2b. The standard intravesicular dose ofBCG is 81 mg for TheraCys® and 50 mg for TICE,® both in 50 ccphysiologic saline. Treatment should be postponed for at least 1 to 2weeks following tumor resection or bladder biopsy. Treatments aretypically repeated weekly for 6 weeks, with dose reductions to ⅓, 1/10,1/30, or 1/100 as needed to prevent increasing or severe symptoms ofbladder irritation. Additional instillations can be given at 3 months (6weeks after completion of the initial 6-week course). Maintenance BCGcan be provided using up to 3 weekly instillations in disease-freepatients given at 3, 6, 12, 18, 24, 30, and 36 months, and at years(counting from the start of treatment) 4, 5, 6, 8, 10, and 12 forpatients with CIS or high-grade disease.

Interferon Alpha 2b, which is relatively non-toxic, has been givenintravesically in doses as high as 1 billion units without dose-limitingside effects. The standard dose is 50 to 100 million units weekly for 6weeks. Additional maintenance treatments can be beneficial.

BCG immunotherapy can be combined with chemotherapy, e.g., mitomycin C.Combination chemotherapy can be used in patients with metastatictransitional cell carcinoma. Combination immunotherapy, specifically theuse of BCG plus interferon alpha2b, can be effective. According toO'Donnell, et al., 2001, “Salvage intravesical therapy withinterferon-alpha 2b plus low dose bacillus Calmette-Guerin is effectivein patients with superficial bladder cancer in whom bacillusCalmette-Guerin alone previously failed,” Journal of Urology,166(4):1300-1304), about 60% of patients who fail to respond to BCG canbe rescued with BCG plus interferon alpha. The standard dose is 50 mg to81 mg of BCG plus 50 million units of interferon alpha 2b. Treatmentsare given weekly for 6 weeks, with maintenance using up to 3 weeklyinstillations at 3 or 6 months, and then every 6 to 12 months. The doseof BCG is reduced to ⅓, 1/10, 1/100 as needed to prevent increased sideeffects.

In embodiments, urinary tract cancers are treated with radiolabeled orcytotoxic GRP analogs using the devices and methods of the invention.High levels of vascular gastrin-releasing peptide (GRP) receptors havebeen reported in urinary tract cancers, making these cancersparticularly suitable for therapies that target the tumor vascular bed.(See, e.g., Fleischmann, et al., June 2009, Endocr. Relat. Cancer,16(2):623-33.)

“Gastrointestinal care” or “GI care” as used herein refers to thetreatment and prevention of diseases and/or ailments of gastrointestinalsystem (GI system) and/or the gastrointestional tract (GI tract), whichcan include treatment and prevention of diseases and/or ailments of theesophagus, stomach, first, second and third part of the duodenum,jejunum, ileum, the ileo-cecal complex, large intestine (ascending,transverse and descending colon) sigmoid colon and rectum. Active agentsare contemplated for use in embodiments of methods and/or devicesprovided herein for gastrointestinal care. Devices and methods providedherein are contemplated for use in Gastrointestinal care.

Upper gastrointestinal disease includes disease of the oral cavity,esophagus, and stomach. Intestinal disease includes disease of the smallintestine, large intestine, disease that affect both the large and smallintestine, and disease of the rectum and anus. Disease of the accessorydigestive glands includes liver, pancreas, gall bladder and bile ductdisease. Other gastrointestinal diseases include, e.g., hernia,peritoneal disease, and gastrointestinal bleeding.

Diseases of the upper gastrointestinal tract include, e.g., esophagitis,which can be caused by candidiasis, rupture (Boerhaave syndrome,Mallory-Weiss syndrome), UES (Zenker's diverticulum), LES—(Barrett'sesophagus), esophageal cancers, bacterial infections, viral infections,esophageal motility disorder (Nutcracker esophagus, Achalasia, Diffuseesophageal spasm, GERD), esophageal stricture, megaesophagus, gastritis(atrophic, Ménétrier's disease, gastroenteritis), peptic (gastric),ulcer (Cushing ulcer, Dieulafoy's lesion), dyspepsia, pyloric stenosis,achlorhydria, gastroparesis, gastroptosis, portal hypertensivegastropathy, gastric antral vascular ectasia, gastric dumping syndrome,and gastric volvulus.

Diseases of the intestine include, e.g., enteritis (duodenitis,jejunitis, ileitis), Peptic (duodenal) ulcer, Curling's ulcer,malabsorption diseases (e.g., coeliac, tropical sprue, blind loopsyndrome, Whipple's, short bowel syndrome, steatorrhea), cancers,bacterial infections, viral infections, appendicitis, colitis(pseudomembranous, ulcerative, ischemic, microscopic, collagenous,lymphocytic), functional colonic disease (IBS, intestinalpseudoobstruction/Ogilvie syndrome), megacolon/toxic megacolon,diverticulitis/diverticulosis, enterocolitis, IBD, Crohn's disease,vascular diseases (e.g., abdominal angina, mesenteric ischemia,angiodysplasia), bowel obstruction (due to, e.g., ileus,intussusception, volvulus), fecal impaction, and diarrhea.

Diseases of the rectum and anus include proctitis, e.g., radiationproctitis, proctalgia fugax, rectal prolapse, anal fissure/anal fistula,anal cancer, and anal abscess.

Diseases of the accessory digestive glands include diseases that affectthe liver, e.g., hepatitis, cirrhosis, fatty liver disease, livercancer, vascular disease (e.g., hepatic veno-occlusive disease, portalhypertension, nutmeg liver), alcoholic liver disease, liver failure,liver abscess, hepatorenal syndrome, peliosis hepatis, hemochromatosis,and Wilson's Disease. Additional accessory digestive gland diseasesinclude pancreatitis (Acute, Chronic, Hereditary), pancreatic cancer,pancreatic pseudocyst, exocrine pancreatic insufficiency, and pancreaticfistula. Gall bladder and bile duct diseases include cancers,cholecystitis, gallstones/cholecystolithiasis, cholesterolosis,Rokitansky-Aschoff sinuses, postcholecystectomy syndrome, cholangitis(PSC, Ascending), cholestasis/Mirizzi's syndrome, biliary fistula,haemobilia, gallstones/cholelithiasis, choledocholithiasis, and biliarydyskinesia.

Other diseases affecting the GI system include hernias, peritonitis,hemoperitoneum, and pneumoperitoneum. GI bleeding diseases include,hematemesis, melena, and hematochezia. Treatment of any GI systemdisease includes administration of drugs in association with surgery orresection, e.g., chemotherapeutic agents, antibiotics, antiinflammatoryagents, or combinations thereof.

In certain embodiments, Ankaferd blood stopper, a medicinal plantextract, is locally delivered to prevent uncontrolled bleeding of apassageway such as the rectum using the devices and methods of theinvention. Nasal passageways can also be treated in a similar manner.Administration of Ankaferd blood stopper is described by, e.g., Kurt, etal., 2009, “Tandem oral, rectal, and nasal administrations of AnkaferdBlood Stopper to control profuse bleeding leading to hemodynamicinstability,” Am. J. Emerg. Med. 27(5):631, e1-2.

In other embodiments, tacrolimus is administered using the devices andmethods of the invention to treat resistant ulcerative proctitis. Theeffect of tacrolimus ointment in controlling ulcerative proctitis hasbeen described, e.g., by Lawrance, et al., Nov. 15, 2008, “Rectaltacrolimus in the treatment of resistant ulcerative proctitis,” Aliment.Pharmacol. Ther. 28(10): 1214-20.

In embodiments, the devices and methods of the invention are used toprotect mucous membranes. For example, the devices and methods of theinvention can be used to deliver topical microbicide, rectally orvaginally, for prevention of transmission of HIV or other STDs. (See,e.g., Hladik, et al., 2008, “Can a topical microbicide prevent rectalHIV transmission?” PLoS Med. 5(8):e167.)

“Respiratory care” as used herein refers to the therapy, management,rehabilitation, diagnostic evaluation and care of patients with actualor suspected diseases, including pathogenic infections, or otherconditions or ailments that affect the upper and/or lower respiratorysystem and associated aspects of other system functions. It includes thetreatment or management of acute and chronic breathing disorders. Activeagents are contemplated for use in embodiments of methods and/or devicesprovided herein for Respiratory care. Devices and methods providedherein are contemplated for use in Respiratory care. Typically, thedisease or condition is a respiratory disease or condition, including,but not limited to, inflammatory airway diseases (e.g., asthma, chronicobstructive pulmonary disease (COPD), bronchiolitis), bronchopulmonarydysplasia, croup, bronchitis, bronchiectasis, emphysema, allergicrhinitis, the pulmonary sequelae of cystic fibrosis, Churg-Strausssyndrome, mycobacterial diseases (caused by, e.g., M. tuberculosis, M.avium), severe acute respiratory syndrome (SARS), and pneumonia. Activeagents are contemplated for use in embodiments of methods and/or devicesprovided herein for respiratory care.

In embodiments, the invention is used for administering agents prior toor during endotracheal intubation. Use of an endotracheal tube orlaryngeal mask can result in significant postoperative sore throat,coughing and hoarseness. Lidocaine and betamethasone have been appliedtopically in gels or sprays to reduce discomfort. Extended, controlled,local delivery controlled local delivery can provide significantlygreater benefit. For example, the endotracheal tube or laryngeal maskcould be coated, fully or partially, with a bioresorbable matrixbetamethasone (0.05%) or another appropriate antiinflammatory agent,and/or lidocaine (2.0-4.0%), or another appropriate anesthetic.Alternately, the coating could be delivered to the tissue via a largeballoon-type catheter prior to insertion of the endotracheal tube orlaryngeal mask.

In related embodiments, compositions can be applied via a drug/polymerdelivery device prior to endoscopic procedures, or applied to theendoscope itself. Topical administration of local anesthetic agents canreduce a rise in blood pressure, decrease the time before a patient candrive or operate machinery, as well as increase comfort during consciousendoscopic procedures such as gastroendoscopy. The use ofantiinflammatory or anesthetic agents has been described by, e.g.:Sumathi, et al., 2008, “Controlled comparison between betamethasone geland lidocaine jelly applied over tracheal tube to reduce postoperativesore throat, cough, and hoarseness of voice,” Br. J. Anaesth. 100(2):215-218; Kazemi, et al., 2007, “The effect of betamethasone gel inreducing sore throat, cough, and hoarsness after laryngo-trachealintubation,” Middle East J Anesthesiol. 19(1):197-204; Minoque, et al.,2004, “Laryngotracheal topicalization with lidocaine before intubationdecreases the incidence of coughing on emergence from generalanesthesia,” Anesth Analg. 99(4):1253-1257; Xue, et al., 2009,“Spray-as-you-go airway topical anesthesia in patients with a difficultairway: a randomized, double-blind comparison of 2% and 4% lidocaine,”Anesth Analg. 108(2): 536-543; Ristikankare, et al., 2006, “Sedation,topical pharyngeal anesthesia and cardiorespiratory safety duringgastroscopy,” J Clin Gastroenterol. 40(10):899-905; and Froehlich, etal., 1995, “Conscious sedation for gastroscopy: patient tolerance andcardiorespiratory parameters,” Gastroenterology 108(3):697-704.

In embodiments, the devices and methods of the invention can be used toprevention tracheal stenosis in upper airway surgery. Topicalapplication of agents including mitomycin C and heparin have beendescribed to improve healing and reduce scarring followinglaryngeal/tracheal surgery. The methods described do not necessarilyprovide sufficient delivery time, or thorough coating of the affectedarea. The devices and methods of the invention can be used for localdelivery of a bioresorbable polymer/drug mixture, wherein the polymerthan can deliver active agent over the course of the normal woundhealing period, e.g., one to three months. This extended delivery cansignificantly reduce the need for additional surgery to treat scarringand stenosis of the upper airways. Current topical applications known tobe safe and somewhat effective use a concentration of about 0.4-0.5mg/ml (˜0.04-0.05%) of mitomycin C or a concentration of heparin ofabout 5000 U/ml.

In these embodiments, the delivery device can be similar to anendotracheal catheter having a balloon coated with the polymer/drugcombination. In further embodiments, one or more repeat procedures areperformed after surgery, as needed, to ensure adequate delivery ofactive agent over the course of the wound healing process. The use ofmitomycin C or heparin for reducing scarring after esophageal ortracheal surgery has been described by, e.g.: Smith, et al., 2009,“Mitomycin C and the endoscopic treatment of laryngotracheal stenosis:are two applications better than one?” Laryngoscope 119(2):272-283; Sen,et al., Feb. 21, 2009, “Topical heparin: A promising agent for theprevention of tracheal stenosis in airway surgery,” J Surg Res [Epubahead of print]; Warner, et al., 2008, “Mitomycin C and airway surgery:how well does it work?” Ontolaryngol Head Neck Surg. 138(6): 700-709.

“Ear-Nose-Throat care” or “ENT care” as used herein refers to diagnosis,treatment and prevention of disorders, including but not limited tocancers, bacterial infections, and viral infections, of the ENT system,which can include the head and neck region, including the ear, nose,throat and paranasal sinuses, as well as disorders of the mouth,salivary glands, vocal cords, larynx, face and neck. ENT disordersinclude, but are not limited to, sinusitis, head and neck cancer, skincancers, disorders or enlargement of the tonsils and adenoids, sleepdisorders, vocal cord disorders, e.g., paralysis, hearing loss andvertigo, and hoarseness. Active agents are contemplated for use inembodiments of methods and/or devices provided herein for ENT care.Devices and methods provided herein are contemplated for use in ENTcare.

In particular embodiments, sinusitis and other sinus disorders aretreated using the methods of the invention. The sinus system consists ofmany different pathways, called ducts or ostia, which allow mucus, airand other substances to drain and flow through the system. Inflammationcan occur in the tissues that make up the ducts and ostia, causing themto swell and block the normal flow. Inflammation may be caused byallergies, noxious agents, nasal polyps, and other factors. Over timethere can be a pathologic increase in inflamed tissue causing permanentdisruption in the flow through the sinus system. Obstruction of thenarrow ducts and ostia between the paranasal sinuses and nasal cavitydevelops, resulting in a vicious cycle of increased secretions, edemaand ultimately complete blockage of the sinus pathways. The state ofchronic sinus inflammation is called sinusitis. Sinusitis can both becaused by and can cause a narrowing of the sinus ostia. In someembodiments, the intervention site is a sinus cavity wall. In someembodiments, the active agent comprises a corticosteroid to treatsinusitis, either alone or in conjunction with an antibiotic agent.Methods for accessing sinus ostia or sinus cavities using devicesincluding balloon catheters, for dilating the ostia of paranasal sinusesare described, e.g., in U.S. Pat. Appl. No. 2009/0076446, “Adjustablecatheter for dilation in the ear, nose or throat,” incorporated hereinby reference in its entirety. In some embodiments, the active agentcomprises a corticosteroid.

In embodiments, agents including but not limited to chemotherapeutic,antibiotic, or antiinflammatory agents or a combination thereof areadministered in the treatment of laryngeal cancer using the devices andmethods of the invention. In other embodiments, the devices and methodsof the invention are used to administer painkillers, antibiotics,botulinum toxin, and/or anti-inflammatory agents in vocal cordmedialization.

In embodiments, the devices and methods of the invention are used toadminister IGF-1 to protect or repair the neurosensory structures in theinner ear. Cochlear administration of IGF-1, delivered locally via ahydrogel to the round window membrane, has been reported to preventhearing loss caused by noise trauma or ischemia. (See, e.g., Fujiwara,et al., “Insulin-like growth factor 1 treatment via hydrogels rescuescochlear hair cells from ischemic injury” 29 Oct. 2008, NeuroReport19(16):1585-1588, and Lee, et al., 2007, “Novel therapy for hearingloss: delivery of insulin-like growth factor 1 to the cochlea usinggelatin hydrogel,” Otol. Neurotol. 28(7):976-81.)

“Ocular care” as used herein refers to the treatment, prevention, anddiagnosis of disorders of the eye and tear duct, including but notlimited to injury (e.g., blunt trauma, abrasion, and trauma due tosurgery), bacterial infection, viral infection, diabetic retinopathy,artery occlusion, glaucoma, chemical exposure, sun damage, keratitis,edema, uveitis, cancers, AMD, vision defects, etc.

For example, the devices and methods of the invention can be used toadminister agents for treatment of infection, e.g., antibiotic oranti-inflammatory agents, between the sclera and the eyelid, between thesclera and the conjunctiva, trancsclerally to the retina, or within thevitreous (intravitreally), using methods known in the art. Glaucoma canbe treated using beta blockers (e.g., levobunolol, timolol, betaxolol,and metipranolol), alpha-agonists (e.g., apraclonidine, brimonidine),carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide),prostaglandin-like compounds, e.g., latanoprost, bimatoprost, andtravoprost, miotic or cholinergic agents (e.g., pilocarpine, carbachol),epinephrine compounds (e.g., dipivefrin), carbonic anhydrase inhibitors(e.g., acetazolamide, methazolamide) or with neuroprotective drugs,e.g., memantine and brimonidine. As is the case in other uses of theinvention, agents typically taken orally can be given at much lowerdoses when administered locally, reducing the occurrence of adverse sideeffects. Unwanted angiogenesis can be treated using, e.g., angiogenesisinhibitors including antisense agents (e.g., Macugen), thalidomide, andEM-138. U.S. Pat. No. 7,524,865, “Methods and compositions for treatingan ocular neovascular disease,” incorporated herein by reference in itsentirety, describes ocular diseases and their treatment usingangiogenesis inhibitors. Accessing the vitreous for drug administrationis described, e.g., in U.S. Pat. No. 7,485,113, “Method for drugdelivery through the vitreous humor,” incorporated herein by referencein its entirety.

“Orthopedic care” as used herein refers to the treatment, prevention,and diagnosis of orthopedic diseases and conditions, including but notlimited to developmental diseases, genetic diseases, injuries,infections, and cancers of the bones (including the spine and spinalcord), muscles, tendons, and joints. Such conditions include diseased,injured, or abnormal cartilage, bursitis, osteonecrosis, carpal tunnelsyndrome, joint pain, and joint injuries, e.g., knee injury. Joint painnot due to injury can be caused by inflammation, for example in gout,sacroiliitis, and arthritis. Examples of types of arthritis that can betreated using the device and methods of the invention includeosteoarthritis, rheumatoid arthritis, and infectious arthritis.Infectious arthritis is commonly caused by Staphylococcus aureus, andalso can be caused by gonorrhea or fungi. Developmental orthopedicdiseases (DOD) include Osteochondritis dissecans, subchondral cysticlesions, physitis, flexural deformities, angular deformities, cuboidalbone disease, and juvenile osteoarthritis. In embodiments, the deviceand methods of the invention are used to treat arthritis pain andneuropathic pain. In other embodiments, the device and methods of theinvention are used to encourage tissue in-growth following, e.g.,injury, surgery, abcess, tumor removal, around orthopedic or cosmeticimplants, etc. For example, agents that can be administered includegrowth hormones, cytokines, e.g., anti-inflammatory agents, stem orregenerative cells, BDNF, fibroblast growth factors, platelet-derivedgrowth factors, growth differentiation factors, bone morphogeneticproteins, transforming growth factors, e.g., TGF-beta1,cartilage-derived morphogenic proteins, vascular endothelial growthfactors, epidermal growth factors, hepatocyte growth factors, insulingrowth factors, angiogenic factors, etc.

In embodiments, the device and methods of the invention are used toadminister therapeutic agents for the treatment of orthopedic diseasesand conditions, either alone, in conjunction with, or in place of, othertherapies and/or surgery and/or diagnostic procedures, including but notlimited to ACL surgery and other knee surgeries, rotator cuff surgery,joint replacement surgery, bone grafts, osteotomy, or coredecompression. Active agents are contemplated for use in embodiments ofmethods and/or devices provided herein for Orthopedic care. Devices andmethods provided herein are contemplated for use in Orthopedic care.

In embodiments, drugs or compounds useful in the devices and methods ofthe invention either alone or in combination for treating orthopedicdiseases and conditions include, but are not limited to, steroids,anti-inflammatory drugs, antibiotics, anti-viral agents, cancer-fightingdrugs (including antioneoplastic, antiproliferative, antimycotic, andantimetabolite compounds), glucocorticoid anti-inflammatories (such asdexamethasone, fluocinolone, cortisone, prednisolone, flumetholone, andderivatives thereof), non-steroidal anti-inflammatory drugs (NSAIDs),immune suppressants, antibiotics, cartilage protectants, diseasemodifying anti-rheumatic drugs (e.g., adalimumab, azathioprine,chloroquine, hydroxychloroquine, cyclosporine, D-penicillamine,etanercept, gold salts, including sodium aurothiomalate and auranofin,infliximab, leflunomide, methotrexate, minocycline, and sulfasalazine),chondroitin sulfate, enzyme inhibitors, and/or antisense compounds suchas antisense oligonucleotides, and pain relieving agents. Specificagents useful in the devices and methods of the invention include, butare not limited to, corticosteroids such as dexamethasone andtriamcinolone acetonide, angiostatic steroids such as anecortaveacetate, antibiotics including ciprofloxacin, non-steroidalanti-inflammatory agents such as indomethacin and flurbiprofen, co-drugsincluding low-solubility co-drugs of salts or conjugates of synergisticpharmacological agents such as suramin/amiloride or 5-FU/THS, BoneMorphogenetic Protein (BMP), cell-based therapies (e.g., stem orregenerative cells), imaging agents, and combinations thereof. Drugs andformulations for treating joint conditions are described, e.g., in U.S.Pat. No. 6,936,270 “Device and method for treating conditions of ajoint,” incorporated herein by reference in its entirety.

In embodiments of the devices and methods of the invention, jointconditions are treated by providing sustained release of at least onetherapeutically effective compound for a duration of about 3 months toabout 10 years. In embodiments, sustained release is provided for about6 months to about 5 years. In certain embodiments, sustained release ofa therapeutically effective compound is provided for about 1 year, 2years, 3 years, or 4 years, or longer. As a result, the need forfrequent, repeated administrations, such as with injections, is avoided.

“Spinal care” as used herein refers to the treatment, prevention, anddiagnosis of spine and spinal cord diseases and conditions, includingbut not limited to developmental and genetic diseases, injuries,infections, and cancers of the spine and spinal cord, including, e.g.,degenerative conditions (e.g., herniated cervical disc, herniated lumbardisc, spondylolysis, spondylolisthesis, stenosis, and osteoporosis),ankylosing spondylitis, Adolescent Idiopathic Scoliosis, spinal cordinjury, spinal infection; spinal tumor, whiplash. Active agents arecontemplated for use in embodiments of methods and/or devices providedherein for Spinal care. Devices and methods provided herein arecontemplated for use in Spinal care.

In embodiments, the device and methods of the invention are used toadminister therapeutic agents for the treatment of spine and spinal corddiseases and conditions, either alone, in conjunction with, or in placeof, other therapies, surgery, diagnostic procedures, and combinationsthereof, including but not limited to discectomy, fusion, laminectomy orlaminotomy, Intradiscal Electrothermal Therapy (IDET), PercutaneousVertebral Augmentation (PVA), Artificial Disc Replacement (ADR),vertebroplasty, joint injections, epidural injections, laparascopicspine surgery, and MRI of the spine.

In embodiments, the devices and methods of the invention are used toadminister agents for sustained release in the treatment of degenerativedisc disease. Agents useful for treatment of degenerative disc diseaseinclude, e.g., MMP inhibitors.

In embodiments, the devices and methods of the invention are used toprovide at least one agent to, e.g., the nucleus pulposus of adegenerating disc, the annulus fibrosus of a degenerating disc, theouter wall of the annulus fibrosus, at a location outside but closelyadjacent to an outer wall of the annulus fibrosus and/or at a locationoutside but closely adjacent to an endplate of an adjacent vertebralbody. Agents and dosages for sustained release treatment of degenerativedisc disease are described in, e.g., U.S. Pat. No. 7,553,827,“Transdiscal administration of cycline compounds,” and U.S. Pat. No.7,429,378, “Transdiscal administration of high affinity anti-MMPinhibitors,” incorporated herein by reference in their entirety.

In embodiments, drugs or compounds useful in the devices and methods ofthe invention either alone or in combination for treating spine andspinal cord diseases and conditions include, but are not limited to, theagents as described herein with regard to orthopedic care. In addition,antibiotics useful for treatment of spinal tuberculosis include, e.g.,combination drug therapy with isoniazid and rifampicin. In embodiments,the devices and methods of the invention are used to administeranalgesics, e.g., morphine, fentanyl, and/or bupivacaine in the epiduralspace of the spinal cord, for treatment of pain resulting from surgery,including but not limited to spinal or other orthopedic surgery,gynecological surgery, abdominal surgery, and other major surgicalprocedures. Appropriate dosages and administration times forepidurally-administered analgesics have been reported and are known tothose of skill in the art. Continuous epidural administration offers asafety advantage over intermittent epidural injections because peak andtrough levels of the analgesic agent are avoided. Furthermore,administration using the devices and methods of the invention avoidscomplications associated with the extended use of an epidural catheter.

“Cosmetic care” as used herein refers to surgical and nonsurgicalprocedures that alter the appearance of body structures, to improve thepatient's appearance and/or for reconstructive or therapeutic purposes.Active agents are contemplated for use in embodiments of methods and/ordevices provided herein for Cosmetic care. Devices and methods providedherein are contemplated for use in Cosmetic care. Cosmetic careprocedures include, but are not limited to, breast augmentation, breastreduction, breast reshaping, body-contouring (e.g., via liposuction orlipectomy), gastric bypass surgery, stomach stapling, Lap Band surgery,abdominoplasty, use of facial fillers, facial implants, neck lift,blepharoplasty, dacryocystorhynostomy, chemical skin resurfacing, laserskin resurfacing, sclerotherapy, phlebectomy, dermabrasion, face lift,lip augmentation and/or restructuring, rhinoplasty, ear restructuring,hair replacement, hair removal, wound, scar, or lesion treatment (e.g.,laser removal of skin cancer tissue), grafting, flap surgery,micropigmentation, tissue expansion, and the use of coatings on tissueexpanders, breast implants, and on solid molded products (forrhinoplasty, chin implants, etc.). Reconstructive procedures areintended to repair or alter the appearance of defects or structuralabnormalities caused by, e.g., congenital defects, developmentalabnormalities, trauma, infection, tumors or disease, and/or meant toimprove body function or a patient's health. Many reconstructive careprocedures also serve a cosmetic purpose, for example, breastreconstruction after full or partial mastectomy, breast reduction toease discomfort, repair of congenital cleft lip and palate, andblepharoplasty (e.g., when dropping eyelids are obscuring a patient'svision).

Cosmetic care procedures, particularly reconstructive proceduresperformed using the devices and/or methods of the invention, may requirethe use of biomedical implants, which are coated with at least onepharmaceutical agent. For example, the devices and methods of theinvention can be used, in conjunction with electrosurgery for tissueablation, to treat a surgery site with agents including but not limitedto antiinflammatory agents, vasoconstrictors (such as epinephrine),antibiotics, painkillers, or combinations thereof in both cosmeticprocedures and non-cosmetic therapeutic procedures. Electrosurgery isdescribed in, e.g., U.S. Pat. No. 7,201,750 “System for treatingarticular cartilage defects,” incorporated herein by reference in itsentirety.

“Canniluzation” or “Cannulize” or “Cannulizable” as used herein refersto the insertion of a cannula or tube, e.g., at or near an interventionsite. “Cannulizable” as used herein refers to a location, e.g., a vesselor other lumen or opening, into which a cannula can be inserted.

“Stimulation” as used herein refers to any mechanical stimulation,chemical stimulation, thermal stimulation, electromagnetic stimulation,and/or sonic stimulation that influences, causes, initiates, and/orresults in the freeing, dissociation, and/or the transfer of the coatingand/or active agent from the substrate.

“Mechanical Stimulation” as used herein refers to use of a mechanicalforce that influences the freeing, dissociation, and/or transfer of thecoating and/or the active agent from the substrate. For example,mechanical stimulation can comprise a shearing force, a compressiveforce, a force exerted on the coating from a substrate side of thecoating, a force exerted on the coating by the substrate, a forceexerted on the coating by an external element, a translation, arotation, a vibration, or a combination thereof. In embodiments, themechanical stimulation comprises balloon expansion, stent expansion,etc. In embodiments, the mechanical stimulation is adapted to augmentthe freeing, dissociation and/or transfer of the coating from thesubstrate. In embodiments, the mechanical stimulation is adapted toinitiate the freeing, dissociation and/or transfer of the coating fromthe substrate. In embodiments, the mechanical stimulation can be adaptedto cause the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, an external element is a part of thesubject. In embodiments, the external element is not part of the device.In embodiments the external element comprises a liquid, e.g., saline orwater. In certain embodiments the liquid is forced between the coatingand the substrate. In embodiments, the mechanical stimulation comprisesa geometric configuration of the substrate that maximizes a shear forceon the coating.

“Chemical Stimulation” as used herein refers to use of a chemical forceto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, chemical stimulation can comprise bulkdegradation, interaction with a bodily fluid, interaction with a bodilytissue, a chemical interaction with a non-bodily fluid, a chemicalinteraction with a chemical, an acid-base reaction, an enzymaticreaction, hydrolysis, or a combination thereof. In embodiments, thechemical stimulation is adapted to augment the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to initiate the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is adapted to cause the freeing, dissociationand/or transfer of the coating from the substrate. In embodiments, thechemical stimulation is achieved through the use of a coating thatcomprises a material that is adapted to transfer, free, and/ordissociate from the substrate when at the intervention site in responseto an in-situ enzymatic reaction resulting in a weak bond between thecoating and the substrate.

“Thermal Stimulation” as used herein refers to use of a thermal stimulusto influence the freeing, dissociation, and/or transfer of the coatingfrom the substrate. For example, thermal stimulation can comprise atleast one of a hot stimulus and a cold stimulus. In embodiments, thermalstimulation comprises at least one of a hot stimulus and a cold stimulusadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, thermal stimulationcomprises at least one of a hot stimulus and a cold stimulus adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In embodiments, thermal stimulation comprises atleast one of a hot stimulus and a cold stimulus adapted to cause thefreeing, dissociation and/or transference of the coating from thesubstrate.

“Electromagnetic Stimulation” as used herein refers to use of anelectromagnetic stimulus to influence the freeing, dissociation, and/ortransfer of the coating from the substrate. For example, theelectromagnetic stimulation is an electromagnetic wave comprising atleast one of, e.g., a radio wave, a micro wave, a infrared wave, nearinfrared wave, a visible light wave, an ultraviolet wave, a X-ray wave,and a gamma wave. In embodiments, the electromagnetic stimulation isadapted to augment the freeing, dissociation and/or transference of thecoating from the substrate. In embodiments, the electromagneticstimulation is adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In embodiments, theelectromagnetic stimulation is adapted to cause the freeing,dissociation and/or transference of the coating from the substrate.

“Sonic Stimulation” as used herein refers to use of a sonic stimulus toinfluence the freeing, dissociation, and/or transfer of the coating fromthe substrate. For example, sonic stimulation can comprise a sound wave,wherein the sound wave is at least one of an ultrasound wave, anacoustic sound wave, and an infrasound wave. In embodiments, the sonicstimulation is adapted to augment the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the sonicstimulation is adapted to initiate the freeing, dissociation and/ortransfer of the coating from the substrate. In embodiments, the sonicstimulation is adapted to cause the freeing, dissociation and/ortransfer of the coating from the substrate.

“Release Agent” as used herein refers to a substance or substratestructure that influences the ease, rate, or extent, of release of thecoating from the substrate. In certain embodiments wherein the device isadapted to transfer a portion of the coating and/or active agent fromthe substrate to the intervention site, the device can be so adapted by,e.g., substrate attributes and/or surface modification of the substrate(for non-limiting example: substrate composition, substrate materials,substrate shape, substrate deployment attributes, substrate deliveryattributes, substrate pattern, and/or substrate texture), the deliverysystem of the substrate and coating (for non-limiting example: controlover the substrate, control over the coating using the delivery system,the type of delivery system provided, the materials of the deliverysystem, and/or combinations thereof), coating attributes and/or physicalcharacteristics of the coating (for non-limiting example: selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute), release agent attributes (for non-limitingexample: through the selection a particular release agent and/or themanner in which the release agent is employed to transfer the coatingand/or the active agent, and/or the amount of the release agent used),and/or a combination thereof. Release agents may include biocompatiblerelease agents, non-biocompatible release agents to aggravate and/orotherwise induce a healing response or induce inflammation, powderrelease agents, lubricants (e.g. ePTFE, sugars, other known lubricants),micronized drugs as the release agent (to create a burst layer after thecoating is freed from the substrate, physical release agents (patterningof the substrate to free the coating, others), and/or agents that changeproperties upon insertion (e.g. gels, lipid films, vitamin E, oil,mucosal adhesives, adherent hydrogels, etc.). Methods of patterning asubstrate are described, e.g., in U.S. Pat. No. 7,537,610, “Method andsystem for creating a textured surface on an implantable medicaldevice.” In embodiments, more than one release agent is used, forexample, the substrate can be patterned and also lubricated. In someembodiments, the release agent comprises a viscous fluid.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

“Extrusion” and/or “Extruded” and/or to “Extrude” as used herein refersto the movement of a substance away from another substance or object,especially upon stimulation, e.g., by a mechanical force. For example,in embodiments of the invention, the coating is extruded from thesubstrate.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, wherein the coating is patterned, and wherein at leasta portion of the coating is adapted to free from the substrate uponstimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, wherein the coating is patterned, and wherein at leasta portion of the coating is adapted to dissociate from the substrateupon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, wherein the coating is patterned, and wherein at leasta portion of the coating is adapted to transfer from the substrate to anintervention site upon stimulation of the coating.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

“Patterned” as used herein in reference to the coating refers to acoating having at least two different shapes. The shapes can be formedby various methods, including for example, etching, masking,electrostatic capture, and/or by the coating methods described herein.For example the coating may have voids that are at least partiallythrough the thickness of the coating. In some embodiments, the voidsextend fully through the coating. The voids may be in a regularconfiguration, or irregular in shape. The voids may form a repeatingconfiguration to form the patterned coating. The voids may have beenremoved from a smooth or solid coating to form a patterned coating. Thecoating may in some embodiments be patterned by having a surface that isribbed, wavy or bumpy. The coating may in some embodiments be patternedby having been cut and/or etched from a coating sheath and/or sheet in aparticular design. The sheath and/or sheet in such embodiments may havebeen formed using the coating methods for manufacture as describedherein. The pattern design may be chosen to improve the freeing,transfer, and/or dissociation from the substrate. The pattern design maybe chosen to improve the transfer and/or delivery to the interventionsite.

Patterned coatings may be created using the methods and processesdescribed herein, for non-limiting example, by providing a substratehaving a patterned design thereon comprising, for example, a materialthat is chosen to selectively capture the coating particles (whetheractive agent, polymer, or other coating particles) to coat only adesired portion of the substrate. This portion that is coated may be thepatterned design of the substrate.

The term “image enhanced polymer” or “imaging agent” as used hereinrefer to an agent that can be used with the devices and methods of theinvention to view at least one component of the coating, either whilethe coating is on the substrate or after it is freed, dissociated and/ortransferred. In embodiments, an image enhanced polymer serves as atracer, allowing the movement or location of the coated device to beidentified, e.g., using an imaging system. In other embodiments, animage enhanced polymer allows the practitioner to monitor the deliveryand movement of a coating component. In embodiments, use of an imageenhanced polymer enables the practitioner to determine the dose of acomponent of the coating (e.g., the active agent) that is freed,dissociated and/or transferred. Information provided by the imageenhanced polymer or imaging agent about the amount of coatingtransferred to the intervention site can allow the practitioner todetermine the rate at which the coating will be released, therebyallowing prediction of dosing over time. Imaging agents may comprisebarium compounds such as, for non-limiting example, barium sulfate.Imaging agents may comprise iodine compounds. Imaging agents maycomprise any compound that improves radiopacity.

In embodiments, an image enhanced polymer is used with the device andmethods of the invention for a purpose including, but not limited to,one or more of the following: monitoring the location of the substrate,e.g., a balloon or other device; assessing physiological parameters,e.g., flow and perfusion; and targeting to a specific molecule. Inembodiments, “smart” agents that activate only in the presence of theirintended target are used with the device and methods of the invention.

In embodiments, imaging agents useful with the device and methods of thepresent invention include, for example: EgadMe (in which agalactopyranose ring is synthesized to protect a Gd(III) ion from bulkwater); conjugated polymer MEH-PPV nanoparticles; bismuth trioxide; nearinfrared (NIR) fluorochromes; bioluminescence agents (e.g., greenfluorescent protein, red fluorescent protein); SPECT radionuclides,e.g., ⁹⁹Tc^(m) (6 h), ¹¹¹In (2.8 days), ¹²³I (13.2 h) and ¹²⁵I (59.5days); PET radionuclides, e.g., ¹⁵O (2.07 min), ¹³N (10 min), ¹¹C (20.3min), ¹⁸F (1.83 h), ¹²⁴I (4.2 days) and ⁹⁴Tc^(m) (53 min); Gd-DTPA(gadolinium diethylenetriamine pentaacetic acid); Echo-Coat, anultrasound imaging agent (STS-Biopolymers); and barium sulfate. Inembodiments employing nanoparticles, it is important that the particlesare small enough to allow renal clearance (e.g. have a hydrodynamicdiameter less than 5.5 nm) and contain non-toxic components, and thatthe material decomposition products can be eliminated from the body. Itis understood that an imaging agent can be conjugated or otherwiseattached or associated with a compound in the coating according tomethods known to those of skill in the art to form an image enhancedpolymer.

Biological imaging agents useful in embodiments of the device andmethods of the present invention are described in, e.g.: U.S. Pat. No.6,077,880, “Highly radiopaque polyolefins and method for making thesame,” which sets forth a highly radiopaque polyolefin; U.S. Pat. No.7,229,837, “Enhanced photophysics of conjugated polymers,” relating tofluorescent ionic conjugated polymers; Dzik-Jurasz, 2003, “Molecularimaging in vivo: an introduction,” The British Journal of Radiology, 76:S98-S109, providing an overview of in vivo molecular imaging methods;von zur Muhlen, et al., 2008, Magnetic Resonance Imaging Contrast AgentTargeted Toward Activated Platelets Allows In Vivo Detection ofThrombosis and Monitoring of Thrombolysis Circulation,” 118:258-267,reporting imaging of activated platelets using an antibody-containingMRI imaging agent; and Green, et al., “Simple conjugated polymernanoparticles as biological labels,” Proc. Roy. Soc. A, published online24 Jun. 2009 doi: 10.1098/rspa.2009.0181, describing the use ofnanoparticles of conjugated polymers in biological imaging; allincorporated herein by reference in their entirety.

Certain Applications of the Technology

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andwherein the device is adapted to free at least a portion of the coatingfrom the substrate upon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of the substrate, wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andwherein the device is adapted to dissociate at least a portion of thecoating from the substrate upon stimulation of the coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andwherein the device is adapted to transfer at least a portion of thecoating from the substrate to an intervention site upon stimulation ofthe coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating is atleast partially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and wherein the device is adapted to free at leasta portion of the coating from the substrate upon stimulation of thecoating.

Provided herein is a medical device comprising: a substrate and acoating on at least a portion of said substrate, wherein said coating isat least partially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and wherein the device is adapted to dissociate atleast a portion of the coating from the substrate upon stimulation ofthe coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating is atleast partially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and wherein the device is adapted to transfer atleast a portion of the coating from the substrate to an interventionsite upon stimulation of the coating.

In some embodiments, the therapeutically desirable morphology comprisesa crystalline form of the pharmaceutical agent that is not amicrocapsule.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein at least a portion of the coatingis adapted to transfer from the substrate to an intervention site. Insome embodiments, the portion of the coating is adapted to transfer fromthe substrate to the intervention site upon stimulation of the coating.In some embodiments, the device is adapted to transfer the portion ofthe coating from the substrate to the intervention site upon stimulationof the substrate. In some embodiments, stimulation of the coating isachieved by stimulation of the substrate. In some embodiments,stimulation of the substrate translates into a stimulation of thecoating to transfer the coating portion from the substrate to theintervention site.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein at least a portion of the activeagent is adapted to transfer from the substrate to an intervention site.In some embodiments, the portion of the active agent is adapted totransfer from the substrate to the intervention site upon stimulation ofthe coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein the device is adapted to transferat least a portion of the coating from the substrate to an interventionsite. In some embodiments, the device is adapted to transfer the portionof the coating (coating portion) from the substrate to the interventionsite upon stimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, and wherein the device is adapted to transferat least a portion of the active agent from the substrate to anintervention site. In some embodiments, the device is adapted totransfer the portion of the active agent from the substrate to theintervention site upon stimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, wherein the device is adapted to free atleast a portion of the coating from the substrate at an interventionsite. In some embodiments, the device is adapted to free the portion ofthe coating from the substrate at the intervention site upon stimulationof the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, wherein the device is adapted to dissociateat least a portion of the coating from the substrate at an interventionsite. In some embodiments, the device is adapted to dissociate theportion of the coating from the substrate at the intervention site uponstimulation of the coating.

Provided herein is a medical device comprising: a substrate; and acoating on at least a portion of said substrate, wherein said coatingcomprises an active agent, wherein the device is adapted to dissociateat least a portion of the coating from the substrate and to deliver saidportion of the coating to an intervention site. In some embodiments, thedevice is adapted to deliver the portion of the coating to theintervention site upon stimulation of the coating.

Provided herein are drug delivery devices and methods that provide (1) adrug or multiple drugs in the form of, for example, films, solidsolutions, particle mixtures containing nano, − micro and/or macroparticles. The particles may be coated particles, polymerized particlescontaining one drug or multiple drugs optionally mixed with a polymer ormultiple polymers. The polymers may be permanent or bioabsorbable.

One embodiment provides a percutaneous medical device with a coatingthat, upon deployment in the body, delivers some or all of the coatingto a specific therapeutic site in the body. The device can be apermanent implant, for example a stent, or a transient device, such as aballoon catheter. Several other types of devices are contemplated in thepresent application. Another embodiment provides intraocular drugdelivery device. Another embodiment provides a surgical tool. Anillustrative but non-exhaustive list of devices contemplated herein isprovided herein.

In one embodiment, delivery of the coating to the tissue at a siteinside the body of a subject occurs by a coating that dissociates fromthe substrate via: (1) plastic deformation of the coating bycompressive, shear, internally generated and/or externally generatedforces, (2) shearing of the coating from the surface of the device, (3)bulk migration of the coating from the device into the tissue, and/or(4) separation from the device due to hydrolysis of the polymer,resulting in a weak bond between the coating and the device. The devicesprovided herein are for the transfer of some or all of the coating fromthe device to the local tissue to provide a targeted therapeutic effect.In some embodiments (need more details of dissociation—from the“stimulation” and other ideas in the claims)

The devices and method provided herein allow for intervention attargeted disease-states that in some embodiments are site-specificmedical indications, including without limitation lesions, occlusions,infections, tumors, regional sites for tumor therapy such asintraperitoneal delivery, local sites of angiogenesis or inflammationsuch as sites within the eye or retina, gingival delivery forperiodontal disease, within the joints in the synovial fluid, in theventricle to delivery to the CNS spinal fluid, and embolic devices thatalso delivery drugs.

The devices and methods provided herein are contemplated to be used inthe treatment of any disease that would benefit from targeted localdelivery of a pharmaceutical and/or active biological agent. Examples ofdiseases include without limitation coronary artery disease, peripheralartery disease (e.g. carotid, femorial, etc), urinary tract obstructionsand/or infections, biliary tract obstructions and/or infections,tumors/cancer, vascular obstructions (e.g. embolisms, lacunar or embolicstroke, varicose veins, etc.), neurological disorders, post-operativeinfections, diseases of the GI tract, diseases of the reproductivesystem (fallopian tubes), diseases of the Ear-Nose-Throat and anydisease associated with an impairment of flow through a body tubularstructure (e.g., dry eye).

In one embodiment, the coating comprises one or more drugs, optionallyone or more adjuncts or excipients and one or more polymer compositions.The polymer compositions may be permanent or bioabsorbable; morepreferably bioabsorbable (e.g.; PLGA based w/1-95% glycolic acidcontent).

One pervasive challenge to alternative technologies to deliver drugs viapercutaneous catheter devices is how to insure that the drug-formulationis not shed during positioning of the device to the therapeutic site. Inother words: how to insure that the drug is not washed off duringinsertion. This challenge leads to an advantage of the current inventionvs. prior art because of the specific use of a polymeric formulation inthe coating and the method of creating the coating and its formulation.

Embodiments provided herein maintain the drug within a mechanicallysound polymeric coating (as opposed to coated as particles or formulatedin a viscous oil), the coating is much more likely to maintain adhesionto the device during insertion. In these embodiments, there is little orno release of the coating until the device is deployed at thetherapeutic site.

For example, and without limitation, the devices and methods providedherein may be advantageously employed in the local treatment of vasculardiseases, the local treatment of internal diseases via providing drug‘upstream’ in the vasculature from disease sites for: infection,oncology, etc., the local or regional treatment of tumors, the localtreatment infections, particularly those that are hard to treat withsystemic antibiotics, for example due to poor circulation to theinfected site (e.g.; orthopedic, extremities in diabetics, etc), thelocal treatment of neurological disorders such as pain ailments.

In embodiments involving vascular diseases, the devices and methodsprovided herein may advantageously employ coating technology to mitigatethe formation of free particles that could become entrained in the bloodstream and cause negative complications such as emboli. For example,some embodiments are based on the utilization of soft coatings thatundergo facile bulk flow under stress. Other embodiments are based onthe utilization of biodegradable materials such as PLGA polymers thatare mechanically sound at the time of implant, then over time degrade tolose their cohesion and/or adhesion to the surface of the device. Yetother embodiments are based on utilization of layered or laminatedcoatings (laminated layers) to directly control the transfer mechanismsof plastic deformation, shear and bulk-migration. Yet other embodimentsuse all three aspects described above.

In some embodiments, the coating comprises laminated layers that allowdirect control of the transfer, freeing, and/or dissociation of thecoating from the substrate. In some embodiments, the coating compriseslaminated layers that allow direct control of the delivering,depositing, and/or tacking of the coating at and/or to the interventionsite. In some embodiments, the coating comprises laminated layers thatallow direct control of the transferring, freeing, depositing, tacking,and/or dissociating of the coating from the substrate, wherein at leastone of the layers comprises the active agent. In some embodiments, thecoating comprises laminated layers that allow direct control of thetransferring, freeing, depositing, tacking, and/or dissociating of thecoating from the substrate, wherein at least one of the layers comprisesthe pharmaceutical agent. The embodiments incorporating a stent form orframework provide the ability to radiographically monitor the stent indeployment. In an alternative embodiment, the inner-diameter of thestent can be masked (e.g. by a non-conductive mandrel). Such maskingwould prevent additional layers from being on the interior diameter(abluminal) surface of the stent. The resulting configuration may bedesirable to provide preferential elution of the drug toward the vesselwall (luminal surface of the stent) where the therapeutic effect ofanti-restenosis is desired, without providing the same antiproliferativedrug(s) on the abluminal surface, where they may retard healing, whichin turn is suspected to be a cause of late-stage safety problems withcurrent DESs.

One particular advantage provided herein for embodiments wherein thedevice is a stent (coronary, peripheral, non-vascular etc.) is theability to deliver the coating to a much greater area/volume of thearterial wall due to the ‘spreading’ of the drug and polymerformulation. This is in contrast to a traditional DES that delivers drugsolely by diffusion of the drug out of the coating that permanentlyremains on the stent strut. This embodiment may provide clinicaladvantages, especially as stent struts advance to thinner and smallerdiameters, of treating more, and more homogenously, the entire site ofarterial injury caused by deployment of the stent.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andfreeing at least a portion of the coating from the substrate uponstimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, anddissociating at least a portion of the coating from the substrate uponstimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein the coating comprises aplurality of layers, wherein at least one layer comprises apharmaceutical agent in a therapeutically desirable morphology, andtransferring at least a portion of the coating from the substrate to theintervention site upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating is at leastpartially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and freeing at least a portion of the coating fromthe substrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating is at leastpartially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and dissociating at least a portion of the coatingfrom the substrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating is at leastpartially continuous, has at least one portion conformal to thesubstrate, and comprises a pharmaceutical agent in a therapeuticallydesirable morphology, and transferring at least a portion of the coatingfrom the substrate to the intervention site upon stimulating the coatingwith a stimulation.

In some embodiments, the therapeutically desirable morphology comprisesa crystalline form of the pharmaceutical agent that is not amicrocapsule.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein said coating comprises anactive agent, and freeing greater than 35% of the coating from thesubstrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein said coating comprises anactive agent, and dissociating greater than 35% of the coating from thesubstrate upon stimulating the coating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, and wherein said coating comprises anactive agent, and transferring greater than 35% of the coating from thesubstrate to the intervention site upon stimulating the coating with astimulation.

In some embodiments, the single stimulation lasts at most 20 seconds. Insome embodiments, the device is adapted to free, dissociate, and/ortransfer substantially all of the coating upon the single stimulation ofthe coating. In some embodiments, substantially all of the coatingfrees, dissociates, and/or transfers from the substrate instantaneouslyupon stimulating the coating.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating comprises anactive agent, and wherein the coating is patterned, and freeing at leasta portion of the coating from the substrate upon stimulating the coatingwith a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating comprises anactive agent, and wherein the coating is patterned, and dissociatng atleast a portion of the coating from the substrate upon stimulating thecoating with a stimulation.

Provided herein is a method comprising providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of said substrate, wherein said coating comprises anactive agent, and wherein the coating is patterned, and transferring atleast a portion of the coating from the substrate to the interventionsite upon stimulating the coating with a stimulation.

In some embodiments, the patterned coating comprises at least twodifferent shapes.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and transferring at least a portion of the coating fromthe substrate to an intervention site. In some embodiments, thetransferring the coating portion (i.e. the portion of the coating) fromthe substrate to the intervention site is upon stimulating the coatingwith a stimulation. In some embodiments, the transferring the coatingportion from the substrate to the intervention site is upon stimulatingthe substrate with a stimulation. In some embodiments, stimulating thecoating is achieved by stimulating the substrate. In some embodiments,stimulating the substrate translates into stimulating the coating totransfer the coating portion from the substrate to the interventionsite.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and transferring at least a portion of the active agentfrom the substrate to an intervention site. In some embodiments, thetransferring the active agent portion (i.e. the portion of the activeagent) from the substrate to the intervention site is upon stimulatingthe coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and freeing at least a portion of the coating from thesubstrate at an intervention site. In some embodiments, the freeing thecoating portion (i.e. the portion of the coating) from the substrate isupon stimulating the coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and dissociating at least a portion of the coating fromthe substrate at an intervention site. In some embodiments, thedissociating the coating portion (i.e. the portion of the coating) fromthe substrate is upon stimulating the coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and depositing at least a portion of the coating at anintervention site. In some embodiments, the depositing the coatingportion (i.e. the portion of the coating) at the intervention site isupon stimulating the coating with a stimulation.

Provided herein is a method comprising: providing a medical device,wherein the medical device comprises a substrate and a coating on atleast a portion of the substrate, wherein the coating comprises anactive agent; and tacking at least a portion of the coating to anintervention site. In some embodiments, the tacking the coating portion(i.e. the portion of the coating) to the intervention site is uponstimulating the coating with a stimulation.

In some embodiments, the substrate comprises a balloon. In someembodiments, the portion of the balloon having coating thereon comprisesan outer surface of the balloon. In some embodiments, the outer surfaceis a surface of the balloon exposed to a coating prior to balloonfolding. In some embodiments, the outer surface is a surface of theballoon exposed to a coating following balloon folding. In someembodiments, the outer surface is a surface of the balloon exposed to acoating following balloon crimping. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at pressuresprovided by inflation of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation at a pressurethat is less than the rated burst pressure of the balloon.

In some embodiments, the coating comprises a material that undergoesplastic deformation at a pressure that is less than the nominalinflation pressure of the balloon. In some embodiments, the coatingcomprises a material that undergoes plastic deformation with at least 8ATM of pressure. In some embodiments, the coating comprises a materialthat undergoes plastic deformation with at least 6 ATM of pressure. Insome embodiments, the coating comprises a material that undergoesplastic deformation with at least 4 ATM of pressure. In someembodiments, the coating comprises a material that undergoes plasticdeformation with at least 2 ATM of pressure.

In some embodiments, the balloon is a compliant balloon. In someembodiments, the balloon is a semi-compliant balloon. In someembodiments, the balloon is a non-compliant balloon. In someembodiments, the balloon conforms to a shape of the intervention site.

In some embodiments, the balloon comprises a cylindrical portion. Insome embodiments, the balloon comprises a substantially sphericalportion. In some embodiments, the balloon comprises a complex shape. Insome embodiments, the complex shape comprises at least one of a doublenoded shape, a triple noded shape, a waisted shape, an hourglass shape,and a ribbed shape.

Some embodiments provide devices that can serve interventional purposesin addition to delivery of therapeutics, such as a cutting balloon. Insome embodiments, the substrate comprises a cutting balloon. In someembodiments, the cutting balloon comprises at least one tacking elementadapted to tack the coating to the intervention site. In someembodiments, the tacking element is adapted to secure the coating to thecutting balloon until inflation of the cutting balloon. In someembodiments, the tacking element comprises a wire. In some embodiments,the wire is shaped in the form of an outward pointing wedge. In someembodiments, the tacking element does not cut tissue at the interventionsite.

One illustration devices provided herein include a cutting balloon forthe treatment of vascular disease (e.g.; occluded lesions in thecoronary or peripheral vasculature). In this embodiment, the coating maybe preferentially located on the ‘cutting wire’ portion of the device.Upon deployment, the wire pushes into the plaque to provide the desiredtherapeutic ‘cutting’ action. During this cutting, the polymer and drugcoating is plastically deformed off of the wire by the combination ofcompressive and shear forces acting on the wire—leaving some or all ofthe coating embedded in the plaque and/or artery wall. A similarapproach may be applied to delivery of oncology drugs (a) directly totumors and/or, (b) to the arteries delivering blood to the tumors forsite-specific chemotherapy, and/or (c) to the voids left after theremoval of a tumor (lumpectomy). These oncology (as well as othernon-vascular) applications may not require the ‘cutting’ aspects andcould be provided by coatings directly onto the balloon or onto a sheathover the balloon or according to an embodiment wherein the coating formsa sheath over the deflated (pleated) balloon.

A cutting balloon embodiment described herein provides severaladvantages. Such embodiment allows for concentrating the mechanicalforce on the coating/wire as the balloon is inflated—the wire may serveto concentrate the point-of-contact-area of the balloon expansionpressure resulting in a much higher force for plastic deformation of thedrug and polymer coating vs. the non-cutting plain balloon which maydistribute the pressure over a much larger area (therefore lower forceproportional to the ratio of the areas). Embodiments involving a cuttingballoon provide for the use of polymers that would otherwise be toorigid (higher modulus) to deform from a non-cutting balloon.

Other embodiments provided herein are based on geometric configurationsof the device that optimize both the deformation and the bulk-migrationof the coating from the device. In one embodiment wherein the device isa cutting balloon, the (coated) wire of the cutting balloon is shapedlike a wedge, pointed outward.

Another embodiment provides catheter-based devices where thedrug-delivery formulation is delivered to the therapeutic site in thevasculature via inflation of a balloon.

One embodiment provides coated percutaneous devices (e.g.; balloons,whether cutting balloons or other balloon types) that, upon deploymentat a specific site in the patient, transfer some or all of thedrug-delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, 90-99%,99-100%) to the site of therapeutic demand. In certain embodiments, theballoon is at least in part cylindrical as expanded or as formed. Incertain embodiments, the balloon is at least in part bulbous as expandedor as formed. In certain embodiments, the balloon is at least in partspherical as expanded or as formed. In certain embodiments, the balloonhas a complex shape as expanded or as formed (such as a double nodedshape, a triple noded shape, has a waist, and/or has an hourglass shape,for non-limiting example).

In some embodiments, the substrate comprises a biomedical implant. Insome embodiments, the substrate comprises a surgical tool.

In some embodiments, the substrate comprises at least one of a stent, ajoint, a screw, a rod, a pin, a plate, a staple, a shunt, a clamp, aclip, a suture, a suture anchor, an electrode, a catheter, a lead, agraft, a dressing, a pacemaker, a pacemaker housing, a cardioverter, acardioverter housing, a defibrillator, a defibrillator housing, aprostheses, an ear drainage tube, an ophthalmic implant, an orthopedicdevice, a vertebral disk, a bone substitute, an anastomotic device, aperivascular wrap, a colostomy bag attachment device, a hemostaticbarrier, a vascular implant, a vascular support, a tissue adhesive, atissue sealant, a tissue scaffold, and an intraluminal device.

In some embodiments, the substrate comprises at least a portion of atool for delivering to the intervention site a biomedical implant,wherein the substrate is the biomedical implant or wherein the substrateis a portion of the device that is not the biomedical implant. In someembodiments, the substrate comprises at least a portion of a tool forperforming a medical procedure. In some embodiments, the tool comprisesat least one of: a knife, a scalpel, a guidewire, a guiding catheter, aintroduction catheter, a distracter, a needle, a syringe, a biopsydevice, an articulator, a Galotti articulator, a bone chisel, a bonecrusher, a cottle cartilage crusher, a bone cutter, a bone distractor,an Ilizarov apparatus, an intramedullary kinetic bone distractor, a bonedrill, a bone extender, a bone file, a bone lever, a bone mallet, a bonerasp, a bone saw, a bone skid, a bone splint, a bone button, a caliper,a cannula, a catheter, a cautery, a clamp, a coagulator, a curette, adepressor, a dilator, a dissecting knife, a distractor, a dermatome,forceps, dissecting forceps, tissue forceps, sponge forceps, boneforceps, Carmalt forceps, Cushing forceps, Dandy forceps, DeBakeyforceps, Doyen intestinal forceps, epilation forceps, Halstead forceps,Kelly forceps, Kocher forceps, mosquito forceps, a hemostat, a hook, anerve hook, an obstetrical hook, a skin hook, a hypodermic needle, alancet, a luxator, a lythotome, a lythotript, a mallet, a partschmallet, a mouth prop, a mouth gag, a mammotome, a needle holder, anoccluder, an osteotome, an Epker osteotome, a periosteal elevator, aJoseph elevator, a Molt periosteal elevator, an Obweg periostealelevator, a septum elevator, a Tessier periosteal elevator, a probe, aretractor, a Senn retractor, a Gelpi retractor, a Weitlaner retractor, aUSA-Army/Navy retractor, an O×Connor-O×Sullivan retractor, a Deaverretractor, a Bookwalter retractor, a Sweetheart retractor, a Joseph skinhook, a Lahey retractor, a Blair (Rollet) retractor, a rigid rakeretractor, a flexible rake retractor, a Ragnell retractor, aLinde-Ragnell retractor, a Davis retractor, a Volkman retractor, aMathieu retractor, a Jackson tracheal hook, a Crile retractor, aMeyerding finger retractor, a Little retractor, a Love Nerve retractor,a Green retractor, a Goelet retractor, a Cushing vein retractor, aLangenbeck retractor, a Richardson retractor, a Richardson-Eastmannretractor, a Kelly retractor, a Parker retractor, a Parker-Mottretractor, a Roux retractor, a Mayo-Collins retractor, a Ribbonretractor, an Alm retractor, a self retaining retractor, a Weitlanerretractor, a Beckman-Weitlaner retractor, a Beckman-Eaton retractor, aBeckman retractor, an Adson retractor, a rib spreader, a rongeur, ascalpel, an ultrasonic scalpel, a laser scalpel, scissors, irisscissors, Kiene scissors, Metzenbaum scissors, Mayo scissors, Tenotomyscissors, a spatula, a speculum, a mouth speculum, a rectal speculum,Sim's vaginal speculum, Cusco's vaginal speculum, a sternal saw, asuction tube, a surgical elevator, a surgical hook, a surgical knife,surgical mesh, a surgical needle, a surgical snare, a surgical sponge, asurgical spoon, a surgical stapler, a suture, a syringe, a tonguedepressor, a tonsillotome, a tooth extractor, a towel clamp, towelforceps, Backhaus towel forceps, Lorna towel forceps, a tracheotome, atissue expander, a subcutaneus inflatable balloon expander, a trephine,a trocar, tweezers, and a venous cliping.

One particular advantage provided herein for embodiments wherein thedevice is a stent (coronary, peripheral, non-vascular etc.) is theability to deliver the coating to a much greater area/volume of thearterial wall due to the ‘spreading’ of the drug and polymerformulation. This is in contrast to a traditional DES that delivers drugsolely by diffusion of the drug out of the coating that permanentlyremains on the stent strut. This embodiment may provide clinicaladvantages, especially as stent struts advance to thinner and smallerdiameters, of treating more, and more homogenously, the entire site ofarterial injury caused by deployment of the stent.

One embodiment provides coated percutaneous devices (e.g.; balloons,whether cutting balloons or other balloons) that, upon deployment at aspecific site in the patient (intervention site), transfer some or allof the drug-delivery formulation (5-10%, 10-25%, 25-50%, 50-90%, 90-99%,99-100%) to the site of therapeutic demand (intervention site). Incertain embodiments, the balloon is at least in part cylindrical asexpanded or as formed. In certain embodiments, the balloon is at leastin part bulbous as expanded or as formed. In certain embodiments, theballoon is at least in part spherical as expanded or as formed. Incertain embodiments, the balloon has a complex shape as expanded or asformed (such as a double noded shape, a triple noded shape, has a waist,and/or has an hourglass shape, for non-limiting example).

Other embodiments provided herein are based on geometric configurationsof the device that optimize both the deformation and the bulk-migrationof the coating from the device. In one embodiment wherein the device isa cutting balloon, the (coated) wire of the cutting balloon is shapedlike a wedge, pointed outward.

In some embodiments, the device comprises a tacking element thatcooperates with the stimulation to tack the coating to the interventionsite. In some embodiments, the device comprises a tacking element thattacks the coating to the substrate until the stimulating.

In some embodiments, the intervention site is in or on the body of asubject. In some embodiments, the intervention site is a vascular wall.In some embodiments, the intervention site is a non-vascular lumen wall.In some embodiments, the intervention site is a vascular cavity wall.

In some embodiments, the intervention site is a wall of a body cavity.In some embodiments, the body cavity is the result of a lumpectomy. Insome embodiments, the intervention site is a cannulized site within asubject.

In some embodiments, the intervention site is a sinus wall. In someembodiments, the intervention site is a sinus cavity wall. In someembodiments, the active agent comprises a corticosteroid.

In some embodiments, the intervention site is located in thereproductive system of a subject. In some embodiments, the device isadapted to aid in fertility. In some embodiments, the device is adaptedto treat a sexually transmitted disease. In some embodiments, the deviceis adapted to substantially prevent pregnancy. In some embodiments, theactive agent comprises a hormone. In some embodiments, the device isadapted to substantially prevent transmission of a sexually transmitteddisease. In some embodiments, the device is adapted to treat an ailmentof the reproductive system.

In some embodiments, the intervention site is located in the urinarysystem of a subject. In some embodiments, the device is adapted to treata disease of the urinary system. In some embodiments, the active agentcomprises fluoroquinolone. In some embodiments, the pharmaceutical agentcomprises fluoroquinolone.

In some embodiments, the intervention site is located at a tumor site.In some embodiments, the tumor site is where a tumor is located. In someembodiments, the tumor site is where a tumor was located prior toremoval and/or shrinkage of the tumor. In some embodiments, the activeagent comprises mitomycin C. In some embodiments, the pharmaceuticalagent comprises mitimycin C.

In some embodiments, the intervention site is located in the ear. Insome embodiments, the intervention site is located in the esophagus. Insome embodiments, the active agent comprises a lidocaine. In someembodiments, the pharmaceutical agent comprises a lidocaine.

In some embodiments, the intervention site is located in the larynx. Insome embodiments, the intervention site is a location of an injury. Insome embodiments, the active agent comprises a betamethasone. In someembodiments, the pharmaceutical agent comprises a betamethasone.

In some embodiments, the intervention site is an infection site. In someembodiments, the infection site is a site wherein an infection mayoccur, and wherein the active agent is capable of substantiallypreventing the infection. In some embodiments, the infection site is asite wherein an infection has occurred, and wherein the active agent iscapable of slowing spread of the infection. In some embodiments, theinfection site is a site wherein an infection has occurred, and whereinthe active agent is capable of treating the infection. In someembodiments, the active agent comprises an anti-infective agent. In someembodiments, the pharmaceutical agent comprises an anti-infective agent.In some embodiments, the anti-infective agent comprises clindamycin.

In some embodiments, the intervention site is a surgery site. In someembodiments, the intervention site is an ocular site.

In some embodiments, the coating is capable of promoting healing. Insome embodiments, the active agent comprises a growth factor. In someembodiments, the growth factor comprises at least one of: an epidermalgrowth factor (EGF), a transforming growth factor-alpha (TGF-alpha), ahepatocyte growth factor (HGF), a vacscular endothelial growth factor(VEGF), a platelet derived growth factor (PDGF), a fibroblast growthfactor 1 (FGF-1), a fibroblast growth factor 2 (FGF-2), a transforminggrowth factor-beta (TGF-beta), and a keratinocyte growth factor (KGF).In some embodiments, the active agent comprises a stem cell.

In some embodiments, the coating is capable of at least one of:retarding healing, delaying healing, and preventing healing. In someembodiments, the coating is capable of at least one of: retarding,delaying, and preventing the inflammatory phase of healing. In someembodiments, the coating is capable of at least one of: retarding,delaying, and preventing the proliferative phase of healing. In someembodiments, the coating is capable of at least one of: retarding,delaying, and preventing the maturation phase of healing. In someembodiments, the coating is capable of at least one of: retarding,delaying, and preventing the remodeling phase of healing. In someembodiments, the active agent comprises an anti-angiogenic agent. Insome embodiments, the coating is capable of releiving pain. In someembodiments, the coating is capable of releiving joint pain. In someembodiments, the coating is capable of blocking pain.

In some embodiments, the coating is a sheath. In some embodiments, thesheath is plastically deformable. In some embodiments, at least aportion of the sheath is capable of being left at the intervention siteupon removal of the substrate from the intervention site. In someembodiments, the substrate is capable of mechanically deforming thesheath at the intervention site.

In some embodiments, the device comprises a retractable sheath. In someembodiments, the sheath is adapted to expose the coating to theintervention site upon retraction.

In some embodiments, the coating comprises a bioadhesive. In someembodiments, the active agent comprises a bioadhesive. In someembodiments, the pharmaceutical agent comprises a bioadhesive. In someembodiments, the coating is adapted to close a vascular puncture. Insome embodiments, the coating aids in closing a vascular puncture. Insome embodiments, the coating is adapated to close a vascular puncture.In some embodiments the active agent comprises a bioadhesive. To close avascular puncture may include sealing the vascular puncture, and/orproviding a seal that closes the vascular puncture. The seal may be thecoating of the device. The bioadhesive may comprise an arylates, and/oran cryanoacrylates. Bioadhesives may also and/or alternatively be calledtissue adhesives. The bioadhesive may comprise n-butyl cyanoacrylate,n-butyl-2-cyanoacrylate, 2-octylcyanoacrylate, and Dermabond, and/orvariations thereof.

Bioadhesives as used herein refer to, in some embodiments, naturalpolymeric materials that act as adhesives. The term “bioadhesive” mayalso and/or alternatively be used to describe a glue formedsynthetically from biological monomers such as sugars, and/or to mean asynthetic material designed to adhere to biological tissue. Bioadhesivesmay consist of a variety of substances, for example: proteins andcarbohydrates. Proteins such as gelatin and carbohydrates such as starchare contemplated herein, as well as syntehtic alternatives to the same.Bioadhesives secreted by microbes and by marine molluscs and crustaceansare contemplated herein.

In some embodiments, the coating substantially prevents adhesion of bodytissue. In some embodiments, the coating promotes prevention of adhesionof body tissue. In some embodiments, the coating comprises hyaluronicacid, hyaluronate, salts, acids, conjugates, and/or derivatives thereof.In some embodiments, the active agent comprises hyaluronic acid,hyaluronate, salts, acids, conjugates, and/or derivatives thereof.

In some embodiments, the device is used to substantially prevent tissueadhesion. In some embodiments, the device is adapted to substantiallyprevent tissue adhesion. To substantially prevent tissue adhesion, asused herein, refers to the ability for the device to, at least in part,block at least a portion of the biologic process that leads to tissueadhesion. To substantially prevent tissue adhesion, as used herein, amyalso and/or alternatively refer to the ability for the device to blockat least a portion of fibrin deposition by the body. To substantiallyprevent tissue adhesion, as used herein, may also and/or alternativelyrefer to the ability for the device to promote dissolving of fibrin. Tosubstantially prevent tissue adhesion, as used herein, may also and/oralternatively refer to the ability for the device to promote bloodcontact with injured tissue. In some embodiments, the device comprises acoating comprising hyaluronic to substantially prevent tissue adhesion.

“Tissue adhesion” as used herein refers to internal scars that may formafter surgury on or between internal organs and/or body tissue. As usedherein, “body tissue” or “tissue” refers to any biologic tissue, whichincludes any ensemble of cells, not necessarily identical. As usedherein, “body tissue” or “tissue” may also or alternatively refer to anyone of muscle tissue, connective tissue, nervous tissue, epithelialtissue, and combinations thereof. Tissue between which adhesions mayform can be of the same tissue type, and/or of different tissue types.

When tissue is injured, the area becomes inflamed. The body responds bydepositing fibrin at the injury site. Fibrin can act like glue betweenthe injury site and nearby tissues, causing them to stick together.Normally, as the body heals, the fibrin dissolves and is replaced withnormal tissue. In some cases, however, decreased blood flow to theinjured tissue prevents the fibrin from dissolving. The result is aninternal scar, also called an adhesion. Adhesions between tissues cantwist and/or pull organs out of their normal positions within the body.This scar tissue may form as a result of injury to organs and tissuesduring surgery. These injuries are typically caused by suturing,cauterization, and abrading tissues and organs during surgery, however,other causes are envisioned herein.

In some embodiments, the device is adapated to close a vascularpuncture. In some embodiments, the coating is adapated to close avascular puncture. In some embodiments the active agent comprises abioadhesive. To close a vascular puncture may include sealing thevascular puncture, and/or providing a seal that closes the vascularpuncture. The seal may be the coating of the device. The bioadhesive mayinclude, but not be limited to: arylates, cryanoacrylates.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, and wherein the device is adapted to free greater than35% of the coating from the substrate upon a single stimulation of thecoating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, and wherein the device is adapted to dissociate greaterthan 35% of the coating from the substrate upon a single stimulation ofthe coating.

Provided herein is a medical device comprising a substrate and a coatingon at least a portion of said substrate, wherein said coating comprisesan active agent, and wherein the device is adapted to transfer greaterthan 35% of the coating from the substrate to an intervention site upona single stimulation of the coating.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent on ths substrate by a dippingand/or a spraying process, wherein forming the coating results ingreater than 35% of the coating being adapted to free from the substrateupon stimulating the coating with a single stimulation.

In some embodiments of the methods and/or devices provided herein, thesingle stimulation lasts at most 20 seconds. In some embodiments of themethods and/or devices provided herein, the device is adapted to freesubstantially all of the coating upon the single stimulation of thecoating. In some embodiments, the single stimulation lasts at most 20seconds. In some embodiments of the methods and/or devices providedherein, substantially all of the coating frees from the substrateinstantaneously upon stimulation of the coating.

“Transfer” or “transference” or “transferring” as used herein in thecontext of the coating refers to the conveyance of all or any part ofthe coating from the substrate to an intervention site. The coating canbe formulated such that part or all of it is transferred from thesubstrate, as desired. Some of the embodiments provided herein are basedon transfer of the coating from the substrate to the body tissueinvolving one or more of (1) plastic deformation by compressive and/orshear force induced by deployment and/or induced by the nativesurrounding tissue and/or induced by the in-growth of new tissuecatalyzed by the deployment of the device (2) shear transfer (wipingoff) of the coating from the device outward (relative to the device)into the tissue, (3) bulk migration, and (4) separation from the devicedue to hydrolysis of the polymer, resulting in a week bond to thedevice. In some embodiments (need more details of dissociation—from the“stimulation” and other ideas in the claims)

Similarly, “transfer” as used herein in the context of the active agentrefers to the conveyance of all or any fraction of an active agent fromthe substrate to an intervention site.

The term “adapted to transfer” a specific portion, e.g., at least about10%, at least about 20%, at least about 30%, greater than 35%, at leastabout 50%, at least about 75%, at least about 85%, at least about 90%,at least about 95%, and/or at least about 99%, of a coating and/oractive agent from the substrate to the intervention site refers to adevice, coating, and/or substrate that is designed to transfer a certainpercentage of its coating to the intervention site.

In some embodiments, the device is adapted to transfer a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the device is so adapted by substrateattributes (for non-limiting example: substrate composition, substratematerials, shape, substrate deployment attributes, substrate deliveryattributes, substrate pattern, and/or substrate texture), the deliverysystem of the substrate and coating (for non-limiting example: controlover the substrate, control over the coating using the delivery system,the type of delivery system provided, the materials of the deliverysystem, and/or combinations thereof), coating attributes (fornon-limiting example: selection of the active agent and/or the polymerand/or the polymer-active agent composition, or by the coating having aparticular pattern—e.g. a ribbed pattern, a textured surface, a smoothsurface, and/or another pattern, coating thickness, coating layers,and/or another physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to transfer a portion ofthe coating and/or active agent from the substrate to the interventionsite. For non-limiting example, the substrate is so adapted by selectionof the substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being transferred.

In some embodiments, the coating is adapted to transfer a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example the coating may be so adapted by selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute.

In some embodiments, the substrate is adapted to transfer a portion ofthe coating and/or active agent from the substrate to the interventionsite. For non-limiting example, the substrate is so adapted by selectionof the substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being transferred.

In some embodiments, the coating is adapted to transfer a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example the coating may be so adapted by selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute.

In some embodiments, transferring at least a portion of the coatingcomprises transferring at least about 10%, at least about 20%, at leastabout 30%, greater than 35%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating from the substrate. In some embodiments,stimulating decreases the contact between the coating and the substrate.In some embodiments, transferring transfers less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, at most about 35%, less than about 50%, less than about 70%, lessthan about 80%, and/or less than about 90% of the coating absentstimulating at least one of the coating and the substrate.

In some embodiments, transferring at least a portion of the active agentcomprises transferring at least about 10%, at least about 20%, at leastabout 30%, greater than 35%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the active agent from the substrate. In some embodiments,stimulating decreases the contact between the coating and the substrate.In some embodiments, transferring transfers less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, at most about 35%, less than about 50%, less than about 70%, lessthan about 80%, and/or less than about 90% of the active agent absentstimulating at least one of the coating and the substrate.

The term “adapted to transfer at least a portion” of the coating oractive agent to an intervention site refers to a device that is designedto transfer any portion of the coating or active agent to anintervention site.

The term “adapted to free” a portion of a coating and/or active agentfrom the substrate refers to a device, coating, and/or substrate that isdesigned to free a certain percentage of the coating and/or active agentfrom the substrate. As used herein, a device, coating, and/or substratethat is designed to free a certain percentage of the coating and/oractive agent from the substrate is designed to unrestrain the coatingand/or active agent from the substrate, and/or to remove any obstructionand/or connection the coating may have to the substrate (whether director indirect).

In some embodiments, the device is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate. For non-limiting examplethe coating may be so adapted by selection of the active agent and/orthe polymer and/or the polymer-active agent composition, or by thecoating having a particular pattern—e.g. a ribbed pattern, a texturedsurface, a smooth surface, and/or another pattern, coating thickness,coating layers, and/or another physical and/or compositional attribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example the coating may be so adapted by selection ofthe active agent and/or the polymer and/or the polymer-active agentcomposition, or by the coating having a particular pattern—e.g. a ribbedpattern, a textured surface, a smooth surface, and/or another pattern,coating thickness, coating layers, and/or another physical and/orcompositional attribute.

In some embodiments, freeing at least a portion of the coating comprisesfreeing at least about 10%, at least about 20%, at least about 30%,greater than 35%, at least about 50%, at least about 75%, at least about85%, at least about 90%, at least about 95%, and/or at least about 99%of the coating from the substrate. In some embodiments, stimulatingdecreases the contact between the coating and the substrate. In someembodiments, freeing frees less than about 1%, less than about 5%, lessthan about 10%. less than about 15%, less than about 25%, at most about35%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulating at leastone of the coating and the substrate.

The term “adapted to dissociate” a portion of a coating and/or activeagent from the substrate refers to a device, coating, and/or substratethat is designed to dissociate a certain percentage of the coatingand/or active agent from the substrate. As used herein, a device,coating, and/or substrate that is designed to dissociate a certainpercentage of the coating and/or active agent from the substrate isdesigned to remove from association between the coating (and/or activeagent) and the substrate. Also and/or alternatively, as used herein, adevice, coating, and/or substrate that is designed to dissociate acertain percentage of the coating and/or active agent from the substrateis designed to separate the coating (and/or active agent) from thesubstrate. This separation may be reversible in some embodiments. Thisseparation may not be reversible in some embodiments.

In some embodiments, the device is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the device is so adapted by substrate attributes (fornon-limiting example: substrate composition, substrate materials, shape,substrate deployment attributes, substrate delivery attributes,substrate pattern, and/or substrate texture), the delivery system of thesubstrate and coating (for non-limiting example: control over thesubstrate, control over the coating using the delivery system, the typeof delivery system provided, the materials of the delivery system,and/or combinations thereof), coating attributes (for non-limitingexample: selection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute), release agentattributes (for non-limiting example: through the selection a particularrelease agent and/or how the release agent is employed to transfer thecoating and/or the active agent, and/or how much of the release agent isused), and/or a combination thereof.

In some embodiments, the substrate is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample, the substrate is so adapted by selection of the substratecomposition, substrate materials, shape, substrate deploymentattributes, substrate delivery attributes, substrate pattern, and/orsubstrate texture, and/or combinations thereof. For example, a ballooncan be designed to only partially inflate within the confines of theintervention site. Partial inflation can prevent a designated portion ofcoating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate. For non-limitingexample the coating may be so adapted by selection of the active agentand/or the polymer and/or the polymer-active agent composition, or bythe coating having a particular pattern—e.g. a ribbed pattern, atextured surface, a smooth surface, and/or another pattern, coatingthickness, coating layers, and/or another physical and/or compositionalattribute.

In some embodiments, the substrate is adapted to free a portion of thecoating and/or active agent from the substrate to the intervention site.For non-limiting example, the substrate is so adapted by selection ofthe substrate composition, substrate materials, shape, substratedeployment attributes, substrate delivery attributes, substrate pattern,and/or substrate texture, and/or combinations thereof. For example, aballoon can be designed to only partially inflate within the confines ofthe intervention site. Partial inflation can prevent a designatedportion of coating from being freed.

In some embodiments, the coating is adapted to dissociate a portion ofthe coating and/or active agent from the substrate to the interventionsite. For non-limiting example the coating may be so adapted byselection of the active agent and/or the polymer and/or thepolymer-active agent composition, or by the coating having a particularpattern—e.g. a ribbed pattern, a textured surface, a smooth surface,and/or another pattern, coating thickness, coating layers, and/oranother physical and/or compositional attribute.

In some embodiments, dissociating at least a portion of the coatingcomprises dissociating at least about 10%, at least about 20%, at leastabout 30%, greater than 35%, at least about 50%, at least about 75%, atleast about 85%, at least about 90%, at least about 95%, and/or at leastabout 99% of the coating from the substrate. In some embodiments,stimulating decreases the contact between the coating and the substrate.In some embodiments, dissociating dissociates less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, at most about 35%, less than about 50%, less than about 70%, lessthan about 80%, and/or less than about 90% of the coating absentstimulating at least one of the coating and the substrate.

“Plastic deformation” as used herein is the change in the physical shapeof the coating by forces induced on the device. Plastic deformationresults in increasing the contact area of the coating on the tissue anddecreasing the contact area of the coating on the device. This change incontact area results in some or all of the coating being preferentiallyexposed to the tissue instead of the device. The terms “plasticdeformation” and “plastically deform,” as used herein in the context ofa coating, are intended to include the expansion of the coating materialbeyond the elastic limit of the material such that the material ispermanently deformed. “Elastic deformation” as used herein refers to areversible alteration of the form or dimensions of the object understress or strain, e.g., inflation pressure of a balloon substrate. Theterms “plastic deformation” and “plastically deform,” as used herein inthe context of a balloon or other substrate, are intended to include theexpansion of the substrate beyond the elastic limit of the substratematerial such that the substrate material is permanently deformed. Onceplastically deformed, a material becomes substantially inelastic andgenerally will not, on its own, return to its pre-expansion size andshape. “Residual plastic deformation” refers to a deformation capable ofremaining at least partially after removal of the inflation stress,e.g., when the balloon is deflated. “Elastic deformation” as used hereinrefers to a reversible alteration of the form or dimensions of theobject (whether it is the coating or the substrate) under stress orstrain, e.g., inflation pressure.

“Shear transfer” as used herein is the force (or component of forces)orthogonal to the device that would drive the coating away from thedevice substrate. This could be induced on the device by deployment,pressure-response from the surrounding tissue and/or in-growth of tissuearound the coating.

“Bulk migration” as used herein is the incorporation of the coatingonto/into the tissue provided by the removal of the device and/orprovided by degradation of the coating over time and/or provided byhydration of the coating over time. Degradation and hydration of thecoating may reduce the coating's cohesive and adhesive binding to thedevice, thereby facilitating transfer of the coating to the tissue.

One embodiment may described by analogy to contact printing whereby abiochemically active ‘ink’ (the polymer+drug coating) from a ‘die’ (thedevice) to the ‘stock’ (the site in the body).

The devices and methods described in conjunction with some of theembodiments provided herein are advantageously based on specificproperties provided for in the drug-delivery formulation. One suchproperty, especially well-suited for non-permanent implants such asballoon catheters, cutting balloons, etc. is ‘soft’ coating thatundergoes plastic deformation at pressures provided by the inflation ofthe balloon (range 2-25 ATM, typically 10-18 ATM). Another suchproperty, especially well-suited to permanent implants such as stents iscoatings where the polymer becomes ‘soft’ at some point after implanteither by hydration or by degradation or by combinations of hydrationand degradation.

Some embodiments provide devices that can advantageously be used inconjunction with methods that can aid/promote the transfer of thecoating. These include introducing stimuli to the coated device onceon-site in the body (where the device is delivered either transiently orpermanently). Such stimuli can be provided to induce a chemical response(light, heat, radiation, etc.) in the coating or can provide mechanicalforces to augment the transfer of the coating into the tissue(ultrasound, translation, rotation, vibration and combinations thereof).

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a mechanical stimulation. In someembodiments, the coating is freed from the substrate using a mechanicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a mechanical stimulation. In some embodiments, thecoating is transferred from the substrate using a mechanicalstimulation. In some embodiments, the coating is transferred to theintervention site using a mechanical stimulation. In some embodiments,the coating is delivered to the intervention site using a mechanicalstimulation. In some embodiments, the mechanical stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the mechanical stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the mechanicalstimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, themechanical stimulation comprises at least one of a compressive force, ashear force, a tensile force, a force exerted on the coating from asubstrate side of the coating, a force exerted on the coating by thesubstrate, a force exerted on the coating from an external element, atranslation, a rotation, a vibration, and a combination thereof. In someembodiments, the external element is a part of the subject. In someembodiments, the external element is not part of the device. In someembodiments, the external element comprises a liquid. In someembodiments, the liquid is forced between the coating and the substrate.In some embodiments, the liquid comprises saline. In some embodiments,the liquid comprises water. In some embodiments, the mechanicalstimulation comprises a geometric configuration of the substrate thatmaximizes a shear force on the coating. In some embodiments, themechanical stimulation comprises a geometric configuration of thesubstrate that increases a shear force on the coating. In someembodiments, the mechanical stimulation comprises a geometricconfiguration of the substrate that enhances a shear force on thecoating.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a chemical stimulation. In someembodiments, the coating is freed from the substrate using a chemicalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a chemical stimulation. In some embodiments, the coatingis transferred from the substrate using a chemical stimulation. In someembodiments, the coating is transferred to the intervention site using achemical stimulation. In some embodiments, the coating is delivered tothe intervention site using a chemical stimulation. In some embodiments,the chemical stimulation comprises at least one of bulk degradation,interaction with a bodily fluid, interaction with a bodily tissue, achemical interaction with a non-bodily fluid, a chemical interactionwith a chemical, an acid-base reaction, an enzymatic reaction,hydrolysis, and combinations thereof. In some embodiments, the chemicalstimulation comprises bulk degradation of the coating. In someembodiments, the chemical stimulation comprises interaction of thecoating or a portion thereof with a bodily fluid. In some embodiments,the chemical stimulation comprises interaction of the coating or aportion thereof with a bodily tissue. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a non-bodily fluid. In some embodiments, the chemicalstimulation comprises a chemical interaction of the coating or a portionthereof with a chemical. In some embodiments, the chemical stimulationcomprises an acid-base reaction. In some embodiments, the chemicalstimulation comprises an enzymatic reaction. In some embodiments, thechemical stimulation comprises hydrolysis.

In some embodiments, the chemical stimulation is adapted to augment thefreeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the chemical stimulation is adapted toinitiate the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the chemical stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the coating comprises amaterial that is adapted to transfer, free, and/or dissociate from thesubstrate when at the intervention site in response to an in-situenzymatic reaction resulting in a weak bond between the coating and thesubstrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate using a thermal stimulation. In someembodiments, the coating is freed from the substrate using a thermalstimulation. In some embodiments, the coating is dissociated from thesubstrate using a thermal stimulation. In some embodiments, the coatingis transferred from the substrate using a thermal stimulation. In someembodiments, the coating is transferred to the intervention site using athermal stimulation. In some embodiments, the coating is delivered tothe intervention site using a thermal stimulation. In some embodiments,the thermal stimulation comprises at least one of a hot stimulus and acold stimulus adapted to augment the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation is adapted to cause the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate. In some embodiments, thethermal stimulation comprises at least one of a hot stimulus and a coldstimulus adapted to initiate the freeing, dissociation and/ortransference of the coating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a electromagnetic stimulation. In someembodiments, the coating is freed from the substrate using aelectromagnetic stimulation. In some embodiments, the coating isdissociated from the substrate using a electromagnetic stimulation. Insome embodiments, the coating is transferred from the substrate using aelectromagnetic stimulation. In some embodiments, the coating istransferred to the intervention site using a electromagneticstimulation. In some embodiments, the coating is delivered to theintervention site using a electromagnetic stimulation. In someembodiments, the electromagnetic stimulation comprises anelectromagnetic wave comprising at least one of a radio wave, a microwave, a infrared wave, near infrared wave, a visible light wave, anultraviolet wave, a X-ray wave, and a gamma wave. In some embodiments,the electromagnetic stimulation is adapted to augment the freeing,dissociation and/or transference of the coating from the substrate. Insome embodiments, the electromagnetic stimulation is adapted to initiatethe freeing, dissociation and/or transference of the coating from thesubstrate. In some embodiments, the electromagnetic stimulation isadapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a sonic stimulation. In some embodiments,the coating is freed from the substrate using a sonic stimulation. Insome embodiments, the coating is dissociated from the substrate using asonic stimulation. In some embodiments, the coating is transferred fromthe substrate using a sonic stimulation. In some embodiments, thecoating is transferred to the intervention site using a sonicstimulation. In some embodiments, the coating is delivered to theintervention site using a sonic stimulation. In some embodiments, thesonic stimulation comprises a sound wave, wherein the sound wave is atleast one of an ultrasound wave, an acoustic sound wave, and aninfrasound wave. In some embodiments, the sonic stimulation is adaptedto augment the freeing, dissociation and/or transference of the coatingfrom the substrate. In some embodiments, the sonic stimulation isadapted to initiate the freeing, dissociation and/or transference of thecoating from the substrate. In some embodiments, the sonic stimulationis adapted to cause the freeing, dissociation and/or transference of thecoating from the substrate.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the device by a combination of at least two of amechanical stimulation, a chemical stimulation, an electromagneticstimulation, and a sonic stimulation.

In some embodiments, the coating is freed, dissociated, and/ortransferred from the substrate by extrusion.

Provided herein are device geometries that maximize the shear forces onthe coating. Such geometric design of the device provides twoadvantages: (1) increases (concentrates) the force to plastically deformthe drug and polymer coating (2) decreases the force of adhesion of thecoating. For example, a wedge-shape aligns the forces of deformationalong a shear plan as opposed to direct compression. This embodimentprovides for: (1) increased efficiency in terms of % of the coatingtransferred (2) increased precision in amount transferred on acase-by-case basis (3) utilization of ‘harder/stiffer’ materials(biopolymers) that would otherwise not deform and/or not bulk-migrateunder deployment conditions (4) minimize the chance of particulateshedding via purposefully designing the shape and direction of both thedeformation and bulk migration. For example for a wedge, particles wouldbe less likely because the coating would be pre-disposed as a shear fromthe device in a sheet form—with the use of soft materials, this may beillustrated as a coating of silicone caulk being extruded from thepressure of a rod being pushed into a mattress.

Another embodiment provide a geometric arrangement of the coatingwhereby layers, e.g. a laminate structure, are provided in the coatingto modulate and control the plastic deformation, shearing andbulk-migration of the coating into the tissue.

One embodiment provides coated substrates that, upon deployment at aspecific site in the patient, transfer some or all of the coating(5-10%, 10-25%, 25-50%, 50-90%, 90-99%, 99-100%) to the site oftherapeutic demand.

In some embodiments, the device further comprises a release agent. Insome embodiments, the release agent is biocompatible. In someembodiments, the release agent is non-biocompatible. In someembodiments, the release agent comprises a powder. In some embodiments,the release agent comprises a lubricant. In some embodiments, therelease agent comprises a surface modification of the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the coating. In some embodiments, the physicalcharacteristic of the coating comprises a pattern. In some embodiments,the pattern is a textured surface on the substrate side of the coating,wherein the substrate side of the coating is the part of the coating onthe substrate. In some embodiments, the pattern is a textured surface onthe intervention site side of the coating, wherein the intervention siteside of the coating is the part of the coating that is transferred to,and/or delivered to, and/or deposited at the intervention site.

In some embodiments, the release agent comprises a viscous fluid. Insome embodiments, the viscous fluid comprises oil. In some embodiments,the viscous fluid is a fluid that is viscous relative to water. In someembodiments, the viscous fluid is a fluid that is viscous relative toblood. In some embodiments, the viscous fluid is a fluid that is viscousrelative to urine. In some embodiments, the viscous fluid is a fluidthat is viscous relative to bile. In some embodiments, the viscous fluidis a fluid that is viscous relative to synovial fluid. In someembodiments, the viscous fluid is a fluid that is viscous relative tosaline. In some embodiments, the viscous fluid is a fluid that isviscous relative to a bodily fluid at the intervention site.

In some embodiments, the release agent comprises a gel.

In some embodiments, the release agent comprises at least one of theactive agent and another active agent. The active agent may be placed onthe substrate prior to the coating in order to act as the release agent.The active agent may be a different active agent than the active agentin the coating. The active agent that is the release agent may providefor a second source of drug to be delivered to the intervention site oranother location once the coating is released from (or transferred from,or freed from, or dissociated from) the substrate.

In some embodiments, the release agent comprises a physicalcharacteristic of the substrate. In some embodiments, the physicalcharacteristic of the substrate comprises at least one of a patternedcoating surface and a ribbed coating surface. In some embodiments, thepatterned coating surface comprises a stent framework. In someembodiments, the ribbed coating surface comprises an undulatingsubstrate surface. In some embodiments, the ribbed coating surfacecomprises an substrate surface having bumps thereon.

In some embodiments, the release agent comprises a property that iscapable of changing at the intervention site. In some embodiments, theproperty comprises a physical property. In some embodiments, theproperty comprises a chemical property. In some embodiments, the releaseagent is capable of changing a property when in contact with at leastone of a biologic tissue and a biologic fluid. In some embodiments, therelease agent is capable of changing a property when in contact with anaqueous liquid.

In some embodiments, the release agent is between the substrate and thecoating.

In some embodiments, substantially all of the coating remains on saidsubstrate until the medical device reaches the intervention site. Insome embodiments, at least about 10%, at least about 20%, at least about30%, at least about 50%, at least about 75%, at least about 85%, atleast about 90%, at least about 95%, and/or at least about 99% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 10% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 20% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 30% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 50% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 75% of the coating is adaptedto transfer from the substrate to the intervention site. In someembodiments, at least about 85% of the coating is adapted to transferfrom the substrate to the intervention site. In some embodiments, atleast about 90% of the coating is adapted to transfer from the substrateto the intervention site. In some embodiments, at least about 95% of thecoating is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 99% of the coating is adaptedto transfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating transferred, or as a variation of thepercentage of the coating transferred).

In some embodiments, the coating portion that is adapted to transferupon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, device is adapted to transferless than about 1%, less than about 5%, less than about 10%. less thanabout 15%, less than about 25%, less than about 50%, less than about70%, less than about 80%, and/or less than about 90% of the coatingabsent stimulation of the coating.

In some embodiments, at least about 10%, at least about 20%, at leastabout 30%, at least about 50%, at least about 75%, at least about 85%,at least about 90%, at least about 95%, and/or at least about 99% of theactive agent is adapted to transfer from the substrate to theintervention site. In some embodiments, at least about 10% of the activeagent is adapted to transfer from the substrate to the interventionsite. In some embodiments, at least about 20% of the active agent isadapted to transfer from the substrate to the intervention site. In someembodiments, at least about 30% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 50% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 75% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 85% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 90% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 95% of the active agent is adapted totransfer from the substrate to the intervention site. In someembodiments, at least about 99% of the active agent is adapted totransfer from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the active agent canmean ranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as apercent of the percentage of the active agent transferred, or as avariation of the percentage of the active agent transferred).

In some embodiments, the active agent portion that is adapted totransfer upon stimulation is on at least one of a distal surface of thesubstrate, a middle surface of the substrate, a proximal surface of thesubstrate, and an abluminal surface of the substrate. In someembodiments, the stimulation decreases the contact between the coatingand the substrate. In some embodiments, the device is adapted totransfer less than about 1%, less than about 5%, less than about 10%.less than about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, and/or less than about 90% of the activeagent absent stimulation of the coating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 10% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 20% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 30% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 50% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 75% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 85% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 90% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 95% of the coating from the substrate to theintervention site. In some embodiments, the device is adapted totransfer at least about 99% of the coating from the substrate to theintervention site. As used herein, “about” when used in reference to apercentage of the coating can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of thecoating transferred, or as a variation of the percentage of the coatingtransferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%,and/or less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, the device is adapted to transfer at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 10% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 20% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 30% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 50% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 75% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 85% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 90% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 95% of the active agent from the substrate tothe intervention site. In some embodiments, the device is adapted totransfer at least about 99% of the active agent from the substrate tothe intervention site. As used herein, “about” when used in reference toa percentage of the active agent can mean ranges of 1%-5%, of 5%-10%, of10%-20%, and/or of 10%-50% (as a percent of the percentage of the activeagent transferred, or as a variation of the percentage of the activeagent transferred).

In some embodiments, the coating portion that transfers upon stimulationis on at least one of a distal surface of the substrate, a middlesurface of the substrate, a proximal surface of the substrate, and anabluminal surface of the substrate. In some embodiments, the stimulationdecreases the contact between the coating and the substrate. In someembodiments, the device is adapted to transfer less than about 1%, lessthan about 5%, less than about 10%. less than about 15%, less than about25%, less than about 50%, less than about 70%, less than about 80%, lessthan about 90% of the active agent absent stimulation of the coating.

In some embodiments, the device is adapted to free at least about 10%,at least about 20%, at least about 30%, at least about 50%, at leastabout 75%, at least about 85%, at least about 90%, at least about 95%,and/or at least about 99% of the coating from the substrate. In someembodiments, the device is adapted to free at least about 10% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 20% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 30% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 50% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 75% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 85% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 90% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 95% of thecoating from the substrate to the intervention site. In someembodiments, the device is adapted to free at least about 99% of thecoating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating freed, or as a variation of thepercentage of the coating freed).

In some embodiments, the coating portion that frees upon stimulation ison at least one of a distal surface of the substrate, a middle surfaceof the substrate, a proximal surface of the substrate, and an abluminalsurface of the substrate.

In some embodiments, the stimulation decreases the contact between thecoating and the substrate. In some embodiments, the device is adapted tofree less than about 1%, less than about 5%, less than about 10%. lessthan about 15%, less than about 25%, less than about 50%, less thanabout 70%, less than about 80%, less than about 90% of the coatingabsent stimulation of the coating.

In some embodiments, the device is adapted to dissociate at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating from the substrate. Insome embodiments, the device is adapted to dissociate at least about 10%of the coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 20% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 30% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 50% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 75% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 85% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 90% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 95% ofthe coating from the substrate to the intervention site. In someembodiments, the device is adapted to dissociate at least about 99% ofthe coating from the substrate to the intervention site. As used herein,“about” when used in reference to a percentage of the coating can meanranges of 1%-5%, of 5%-10%, of 10%-20%, and/or of 10%-50% (as a percentof the percentage of the coating dissociated, or as a variation of thepercentage of the coating dissociated).

In some embodiments, the coating portion that dissociates uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments,stimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to dissociate less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, the device is adapted to deliver at least about10%, at least about 20%, at least about 30%, at least about 50%, atleast about 75%, at least about 85%, at least about 90%, at least about95%, and/or at least about 99% of the coating to the intervention site.In some embodiments, the device is adapted to deliver at least about 10%of the coating to the intervention site. In some embodiments, the deviceis adapted to deliver at least about 20% of the coating to theintervention site. In some embodiments, the device is adapted to deliverat least about 30% of the coating to the intervention site. In someembodiments, the device is adapted to deliver at least about 50% of thecoating to the intervention site. In some embodiments, the device isadapted to deliver at least about 75% of the coating to the interventionsite. In some embodiments, the device is adapted to deliver at leastabout 85% of the coating to the intervention site. In some embodiments,the device is adapted to deliver at least about 90% of the coating tothe intervention site. In some embodiments, the device is adapted todeliver at least about 95% of the coating to the intervention site. Insome embodiments, the device is adapted to deliver at least about 99% ofthe coating to the intervention site. As used herein, “about” when usedin reference to a percentage of the coating can mean ranges of 1%-5%, of5%-10%, of 10%-20%, and/or of 10%-50% (as a percent of the percentage ofthe coating delivered, or as a variation of the percentage of thecoating delivered).

In some embodiments, the coating portion that is delivered uponstimulation is on at least one of a distal surface of the substrate, amiddle surface of the substrate, a proximal surface of the substrate,and an abluminal surface of the substrate. In some embodiments, thestimulation decreases the contact between the coating and the substrate.In some embodiments, the device is adapted to deliver less than about1%, less than about 5%, less than about 10%. less than about 15%, lessthan about 25%, less than about 50%, less than about 70%, less thanabout 80%, less than about 90% of the coating absent stimulation of thecoating.

In some embodiments, the active agent comprises a pharmaceutical agent.

In some embodiments, the pharmaceutical agent comprises a macrolideimmunosuppressive drug. In some embodiments the macrolideimmunosuppressive drug comprises one or more of rapamycin,40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin,40-O-(4′-Hydroxymethyl)benzyl-rapamycin,40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin,40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin,40-O-(3-Hydroxy)propyl-rapamycin 4O—O-(6-Hydroxy)hexyl-rapamycin40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin4O—O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,4O—O-(2-Acetoxy)ethyl-rapamycin 4O—O-(2-Nicotinoyloxy)ethyl-rapamycin,4O—O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin4O—O-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-O-Desmethyl-39,40-O,O-ethylene-rapamycin,(26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin,4O—O-(2-Aminoethyl)-rapamycin, 4O—O-(2-Acetaminoethyl)-rapamycin4O—O-(2-Nicotinamidoethyl)-rapamycin,4O—O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,4O—O-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-O-(2′-Tolylsulfonamidoethyl)-rapamycin,40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).

In some embodiments of the methods and/or devices provided herein, themacrolide immunosuppressive drug is at least 50% crystalline. In someembodiments, the macrolide immunosuppressive drug is at least 75%crystalline. In some embodiments, the macrolide immunosuppressive drugis at least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the macrolide immunosuppressive drug is at least95% crystalline. In some embodiments of the methods and/or devicesprovided herein the macrolide immunosuppressive drug is at least 97%crystalline. In some embodiments of the methods and/or devices providedherein macrolide immunosuppressive drug is at least 98% crystalline. Insome embodiments of the methods and/or devices provided herein themacrolide immunosuppressive drug is at least 99% crystalline.

In some embodiments of the methods and/or devices provided hereinwherein the pharmaceutical agent is at least 50% crystalline. In someembodiments of the methods and/or devices provided herein thepharmaceutical agent is at least 75% crystalline. In some embodiments ofthe methods and/or devices provided herein the pharmaceutical agent isat least 90% crystalline. In some embodiments of the methods and/ordevices provided herein the pharmaceutical agent is at least 95%crystalline. In some embodiments of the methods and/or devices providedherein the pharmaceutical agent is at least 97% crystalline. In someembodiments of the methods and/or devices provided herein pharmaceuticalagent is at least 98% crystalline. In some embodiments of the methodsand/or devices provided herein the pharmaceutical agent is at least 99%crystalline.

In some embodiments, the pharmaceutical agent is agent is selected formthe group consisting of In some embodiments, a pharmaceutical agent isat least one of: Acarbose, acetylsalicylic acid, acyclovir, allopurinol,alprostadil, prostaglandins, amantadine, ambroxol, amlodipine,S-aminosalicylic acid, amitriptyline, atenolol, azathioprine,balsalazide, beclomethasone, betahistine, bezafibrate, diazepam anddiazepam derivatives, budesonide, bufexamac, buprenorphine, methadone,calcium salts, potassium salts, magnesium salts, candesartan,carbamazepine, captopril, cetirizine, chenodeoxycholic acid,theophylline and theophylline derivatives, trypsins, cimetidine,clobutinol, clonidine, cotrimoxazole, codeine, caffeine, vitamin D andderivatives of vitamin D, colestyramine, cromoglicic acid, coumarin andcoumarin derivatives, cysteine, ciclosporin, cyproterone, cytabarine,dapiprazole, desogestrel, desonide, dihydralazine, diltiazem, ergotalkaloids, dimenhydrinate, dimethyl sulphoxide, dimeticone, domperidoneand domperidan derivatives, dopamine, doxazosin, doxylamine,benzodiazepines, diclofenac, desipramine, econazole, ACE inhibitors,enalapril, ephedrine, epinephrine, epoetin and epoetin derivatives,morphinans, calcium antagonists, modafinil, orlistat, peptideantibiotics, phenytoin, riluzoles, risedronate, sildenafil, topiramate,estrogen, progestogen and progestogen derivatives, testosteronederivatives, androgen and androgen derivatives, ethenzamide,etofenamate, etofibrate, fenofibrate, etofylline, famciclovir,famotidine, felodipine, fentanyl, fenticonazole, gyrase inhibitors,fluconazole, fluarizine, fluoxetine, flurbiprofen, ibuprofen,fluvastatin, follitropin, formoterol, fosfomicin, furosemide, fusidicacid, gallopamil, ganciclovir, gemfibrozil, ginkgo, Saint John's wort,glibenclamide, urea derivatives as oral antidiabetics, glucagon,glucosamine and glucosamine derivatives, glutathione, glycerol andglycerol derivatives, hypothalamus hormones, guanethidine, halofantrine,haloperidol, heparin (and derivatives), hyaluronic acid, hydralazine,hydrochlorothiazide (and derivatives), salicylates, hydroxyzine,imipramine, indometacin, indoramine, insulin, iodine and iodinederivatives, isoconazole, isoprenaline, glucitol and glucitolderivatives, itraconazole, ketoprofen, ketotifen, lacidipine,lansoprazole, levodopa, levomethadone, thyroid hormones, lipoic acid(and derivatives), lisinopril, lisuride, lofepramine, loperamide,loratadine, maprotiline, mebendazole, mebeverine, meclozine, mefenamicacid, mefloquine, meloxicam, mepindolol, meprobamate, mesalazine,mesuximide, metamizole, metformin, methylphenidate, metixene,metoprolol, metronidazole, mianserin, miconazole, minoxidil,misoprostol, mizolastine, moexipril, morphine and morphine derivatives,evening primrose, nalbuphine, naloxone, tilidine, naproxen, narcotine,natamycin, neostigmine, nicergoline, nicethamide, nifedipine, niflumicacid, nimodipine, nimorazole, nimustine, nisoldipine, adrenaline andadrenaline derivatives, novamine sulfone, noscapine, nystatin,olanzapine, olsalazine, omeprazole, omoconazole, oxaceprol, oxiconazole,oxymetazoline, pantoprazole, paracetamol (acetaminophen), paroxetine,penciclovir, pentazocine, pentifylline, pentoxifylline, perphenazine,pethidine, plant extracts, phenazone, pheniramine, barbituric acidderivatives, phenylbutazone, pimozide, pindolol, piperazine, piracetam,pirenzepine, piribedil, piroxicam, pramipexole, pravastatin, prazosin,procaine, promazine, propiverine, propranolol, propyphenazone,protionamide, proxyphylline, quetiapine, quinapril, quinaprilat,ramipril, ranitidine, reproterol, reserpine, ribavirin, risperidone,ritonavir, ropinirole, roxatidine, ruscogenin, rutoside (andderivatives), sabadilla, salbutamol, salmeterol, scopolamine,selegiline, sertaconazole, sertindole, sertralion, silicates,simvastatin, sitosterol, sotalol, spaglumic acid, spirapril,spironolactone, stavudine, streptomycin, sucralfate, sufentanil,sulfasalazine, sulpiride, sultiam, sumatriptan, suxamethonium chloride,tacrine, tacrolimus, taliolol, taurolidine, temazepam, tenoxicam,terazosin, terbinafine, terbutaline, terfenadine, terlipressin,tertatolol, teryzoline, theobromine, butizine, thiamazole,phenothiazines, tiagabine, tiapride, propionic acid derivatives,ticlopidine, timolol, tinidazole, tioconazole, tioguanine, tioxolone,tiropramide, tizanidine, tolazoline, tolbutamide, tolcapone, tolnaftate,tolperisone, topotecan, torasemide, tramadol, tramazoline, trandolapril,tranylcypromine, trapidil, trazodone, triamcinolone derivatives,triamterene, trifluperidol, trifluridine, trimipramine, tripelennamine,triprolidine, trifosfamide, tromantadine, trometamol, tropalpin,troxerutine, tulobuterol, tyramine, tyrothricin, urapidil, valaciclovir,valproic acid, vancomycin, vecuronium chloride, Viagra, venlafaxine,verapamil, vidarabine, vigabatrin, viloazine, vincamine, vinpocetine,viquidil, warfarin, xantinol nicotinate, xipamide, zafirlukast,zalcitabine, zidovudine, zolmitriptan, zolpidem, zoplicone, zotipine,amphotericin B, caspofungin, voriconazole, resveratrol, PARP-1inhibitors (including imidazoquinolinone, imidazpyridine, andisoquinolindione, tissue plasminogen activator (tPA), melagatran,lanoteplase, reteplase, staphylokinase, streptokinase, tenecteplase,urokinase, abciximab (ReoPro), eptifibatide, tirofiban, prasugrel,clopidogrel, dipyridamole, cilostazol, VEGF, heparan sulfate,chondroitin sulfate, elongated “RGD” peptide binding domain, CD34antibodies, cerivastatin, etorvastatin, losartan, valartan,erythropoietin, rosiglitazone, pioglitazone, mutant protein Apo A1Milano, adiponectin, (NOS) gene therapy, glucagon-like peptide 1,atorvastatin, and atrial natriuretic peptide (ANP), lidocaine,tetracaine, dibucaine, hyssop, ginger, turmeric, Arnica montana,helenalin, cannabichromene, rofecoxib, hyaluronidase, and salts,derivatives, isomers, racemates, diastereoisomers, prodrugs, hydrate,ester, or analogs thereof.

In some embodiments, the pharmaceutical agent comprises hyaluronidase.

In some embodiments, the pharmaceutical agent comprises cilostazol.

In some embodiments, the pharmaceutical agent comprises dipyridamole.

In some embodiments, the pharmaceutical agent comprises an antibioticagent.

In some embodiments, the pharmaceutical agent comprises achemotherapeutic agent.

In some embodiments, the pharmaceutical agent is in a therapeuticallydesirable morphology.

In certain embodiments, a device of the invention is used for treatmentof cancer.

In certain embodiments, devices and methods of the invention are usedfor intraductal treatment of breast cancer. In these embodiments, thedevice is introduced into a breast duct using a delivery tool, e.g., ahollow needle such as a cannula, biopsy needle, or the like into theduct to contact target ductal epithelial cells lining the duct. Theamount of agent can vary, but optimally will be an amount sufficient totarget all atypical or malignant cells in the duct. Estimates of thequantity of target cells can be made upon the initial identification ofthe target duct, e.g. by cytological evaluation of ductal epithelialcells retrieved from the duct. The amount may vary depending on theagent's potency and other mitigating factors such as the extent of anytime delay of delivery of the agent once inside the duct (e.g. with atime release formulation).

In embodiments, a breast cancer is treated using the devices and methodsof the invention to deliver a chemotherapeutic or other appropriateagent as known in the art within the tumor resective cavity followinglumpectomy. In these embodiments a balloon catheter is inserted into thecavity and inflated using methods similar to those used for delivery ofinternal radiation therapy using the MammoSite® RTS.

The agent delivered can be a therapeutically active agent, includinge.g., any agent suitable for treating the breast condition identified,including e.g., any anti-cancer agents, any prophylactic agents, or anyagent for treating any other breast condition or for prophylaxis againsta breast condition. Thus, for example, the agent if an anti-cancer agentcan include, e.g., an estrogen activity modulator, a cytostatic agent,or a cytotoxic agent. The agent may also include e.g., an antibody, apeptide, a polypeptide, a nucleic acid, a polynucleotide, a smallorganic molecule, a macromolecule, a polymer, a carbohydrate, or alipid. The agent can be formulated to be released over time into abreast duct. The agent can be delivered to the lactiferous sinus of thebreast duct for release into the rest of the ductal system from there,or the agent may be delivered to any part of the breast duct, e.g.,including the ductal lumens of the ductal system and also the terminalductal lobular unit. Methods and devices for intraductal treatment ofbreast cancer have been described, e.g., in U.S. Pat. App. No.2004/0147904, “Methods and devices for delivery of agents to breast milkducts,” and WO 02/078716, “Intraductal Treatment Targeting MethylatedPromoters in Breast Cancer,” both incorporated herein by reference intheir entirety.

In some embodiments, the active agent comprises a chemotherapeuticagent. In some embodiments, the pharmaceutical agent comprises achemotherapeutic agent. In some embodiments, the chemotherapeutic agentcomprises at least one of: an angiostatin, DNA topoisomerase,endostatin, genistein, ornithine decarboxylase inhibitors, chlormethine,melphalan, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine (BCNU), streptozocin,6-mercaptopurine, 6-thioguanine, Deoxyco-formycin, IFN-α,17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone,fluoxymesterone, dromostanolone propionate, testolactone,megestrolacetate, methylprednisolone, methyl-testosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, estramustine,medroxyprogesteroneacetate, flutamide, zoladex, mitotane,hexamethylmelamine, indolyl-3-glyoxylic acid derivatives, (e.g.,indibulin), doxorubicin and idarubicin, plicamycin (mithramycin) andmitomycin, mechlorethamine, cyclophosphamide analogs,trazenes-dacarbazinine (DTIC), pentostatin and 2-chlorodeoxyadenosine,letrozole, camptothecin (and derivatives), navelbine, erlotinib,capecitabine, acivicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, ambomycin, ametantrone acetate, anthramycin, asperlin,azacitidine, azetepa, azotomycin, batimastat, benzodepa, bisnafide,bisnafide dimesylate, bizelesin, bropirimine, cactinomycin, calusterone,carbetimer, carubicin hydrochloride, carzelesin, cedefingol, celecoxib(COX-2 inhibitor), cirolemycin, crisnatol mesylate, decitabine,dexormaplatin, dezaguanine mesylate, diaziquone, duazomycin, edatrexate,eflomithine, elsamitrucin, enloplatin, enpromate, epipropidine,erbulozole, etanidazole, etoprine, flurocitabine, fosquidone,lometrexol, losoxantrone hydrochloride, masoprocol, maytansine,megestrol acetate, melengestrol acetate, metoprine, meturedepa,mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitosper,mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran,pegaspargase, peliomycin, pentamustine, perfosfamide, piposulfan,plomestane, porfimer sodium, porfiromycin, puromycin, pyrazofurin,riboprine, safingol, simtrazene, sparfosate sodium, spiromustine,spiroplatin, streptonigrin, sulofenur, tecogalan sodium, taxotere,tegafur, teloxantrone hydrochloride, temoporfin, thiamiprine,tirapazamine, trestolone acetate, triciribine phosphate, trimetrexateglucuronate, tubulozole hydrochloride, uracil mustard, uredepa,verteporfin, vinepidine sulfate, vinglycinate sulfate, vinleurosinesulfate, vinorelbine tartrate, vinrosidine sulfate, zeniplatin,zinostatin, 20-epi-1,25 dihydroxyvitamin D3, 5-ethynyluracil,acylfulvene, adecypenol, ALL-TK antagonists, ambamustine, amidox,amifostine, aminolevulinic acid, amrubicin, anagrelide, andrographolide,antagonist D, antagonist G, antarelix, anti-dorsalizing morphogeneticprotein-1, antiandrogen, antiestrogen, estrogen agonist, apurinic acid,ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane,atrimustine, axinastatin 1, axinastatin 2, axinastatin 3, azasetron,azatoxin, azatyrosine, baccatin III derivatives, balanol, BCR/ABLantagonists, benzochlorins, benzoylstaurosporine, beta lactamderivatives, beta-alethine, betaclamycin B, betulinic acid, bFGFinhibitor, bisaziridinylspermine, bistratene A, breflate, buthioninesulfoximine, calcipotriol, calphostin C, carboxamide-amino-triazole,carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived inhibitor,casein kinase inhibitors (ICOS), castanospermine, cecropin B,cetrorelix, chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin,clomifene analogues, clotrimazole, collismycin A, collismycin B,combretastatin A4, combretastatin analogue, conagenin, crambescidin 816,cryptophycin 8, cryptophycin A derivatives, curacin A,cyclopentanthraquinones, cycloplatam, cypemycin, cytolytic factor,cytostatin, dacliximab, dehydrodidemnin B, dexamethasone, dexifosfamide,dexrazoxane, dexverapamil, didemnin B, didox, diethylnorspermine,dihydro-5-azacytidine, dihydrotaxol, 9-, dioxamycin, docosanol,dolasetron, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine,edrecolomab, elemene, emitefur, estramustine analogue, filgrastim,flavopiridol, flezelastine, fluasterone, fluorodaunorunicinhydrochloride, forfenimex, gadolinium texaphyrin, galocitabine,gelatinase inhibitors, glutathione inhibitors, hepsulfam, heregulin,hexamethylene bisacetamide, hypericin, ibandronic acid, idramantone,ilomastat, imatinib (e.g., Gleevec), imiquimod, immunostimulantpeptides, insulin-like growth factor-1 receptor inhibitor, interferonagonists, interferons, interleukins, iobenguane, iododoxorubicin,ipomeanol, 4-, iroplact, irsogladine, isobengazole, isohomohalicondrinB, itasetron, jasplakinolide, kahalalide F, lamellarin-N triacetate,leinamycin, lenograstim, lentinan sulfate, leptolstatin, leukemiainhibiting factor, leukocyte alpha interferon,leuprolide+estrogen+progesterone, linear polyamine analogue, lipophilicdisaccharide peptide, lipophilic platinum compounds, lissoclinamide 7,lobaplatin, lombricine, loxoribine, lurtotecan, lutetium texaphyrin,lysofylline, lytic peptides, maitansine, mannostatin A, marimastat,maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors,meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone,miltefosine, mirimostim, mitoguazone, mitotoxin fibroblast growthfactor-saporin, mofarotene, molgramostim, Erbitux, human chorionicgonadotrophin, monophosphoryl lipid A+myobacterium cell wall sk, mustardanticancer agent, mycaperoxide B, mycobacterial cell wall extract,myriaporone, N-acetyldinaline, N-substituted benzamides, nagrestip,naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin,nemorubicin, neridronic acid, nisamycin, nitric oxide modulators,nitroxide antioxidant, nitrullyn, oblimersen (Genasense),O⁶-benzylguanine, okicenone, onapristone, ondansetron, oracin, oralcytokine inducer, paclitaxel analogues and derivatives, palauamine,palmitoylrhizoxin, pamidronic acid, panaxytriol, panomifene, parabactin,peldesine, pentosan polysulfate sodium, pentrozole, perflubron, perillylalcohol, phenazinomycin, phenylacetate, phosphatase inhibitors,picibanil, pilocarpine hydrochloride, placetin A, placetin B,plasminogen activator inhibitor, platinum complex, platinum compounds,platinum-triamine complex, propyl bis-acridone, prostaglandin J2,proteasome inhibitors, protein A-based immune modulator, protein kinaseC inhibitors, microalgal, pyrazoloacridine, pyridoxylated hemoglobinpolyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, rasfarnesyl protein transferase inhibitors, ras-GAP inhibitor, retelliptinedemethylated, rhenium Re 186 etidronate, ribozymes, RII retinamide,rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, saintopin,SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetics, senescence derivedinhibitor 1, signal transduction inhibitors, sizofiran, sobuzoxane,sodium borocaptate, solverol, somatomedin binding protein, sonermin,sparfosic acid, spicamycin D, splenopentin, spongistatin 1, squalamine,stipiamide, stromelysin inhibitors, sulfinosine, superactive vasoactiveintestinal peptide antagonist, suradista, suramin, swainsonine,tallimustine, tazarotene, tellurapyrylium, telomerase inhibitors,tetrachlorodecaoxide, tetrazomine, thiocoraline, thrombopoietin,thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist,thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin,titanocene bichloride, topsentin, translation inhibitors, tretinoin,triacetyluridine, tropisetron, turosteride, ubenimex, urogenitalsinus-derived growth inhibitory factor, variolin B, velaresol, veramine,verdins, vinxaltine, vitaxin, zanoterone, zilascorb, zinostatinstimalamer, acanthifolic acid, aminothiadiazole, anastrozole,bicalutamide, brequinar sodium, capecitabine, carmofur, Ciba-GeigyCGP-30694, cladribine, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, cytarabine ocfosfate, Lilly DATHF,Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox,Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015,fazarabine, floxuridine, fludarabine, fludarabine phosphate,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152,5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011, LillyLY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine,nolvadex, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567,Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi ChemicalPL-AC, stearate, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF,trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinaseinhibitors, Taiho UFT, uricytin, Shionogi 254-S, aldo-phosphamideanalogues, altretamine, anaxirone, Boehringer Mannheim BBR-2207,bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine(BiCNU), Chinoin-139, Chinoin-153, chlorambucil, cisplatin,cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate,dacarbazine, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Chugai DWA-2114R, ITI E09,elmustine, Erbamont FCE-24517, estramustine phosphate sodium, etoposidephosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam,ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol,mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, thiotepa, Yakult Honsha SN-22,spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol, Taiho 4181-A, aclarubicin,actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative,Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins,anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859,Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-MyersBMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B,Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A1, esperamicin-A1b,Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitomycinanalogues, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon KayakuNK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine,oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin,pyrindamycin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin,sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, Snow BrandSN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SSPharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B,Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine,tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405,Yoshitomi Y-25024, zorubicin, 5-fluorouracil (5-FU), the peroxidateoxidation product of inosine, adenosine, or cytidine with methanol orethanol, cytosine arabinoside (also referred to as Cytarabin, araC, andCytosar), 5-Azacytidine, 2-Fluoroadenosine-5′-phosphate (Fludara, alsoreferred to as FaraA), 2-Chlorodeoxyadenosine, Abarelix, Abbott A-84861,Abiraterone acetate, Aminoglutethimide, Asta Medica AN-207, Antide,Chugai AG-041R, Avorelin, aseranox, Sensus B2036-PEG, buserelin, BTGCB-7598, BTG CB-7630, Casodex, cetrolix, clastroban, clodronatedisodium, Cosudex, Rotta Research CR-1505, cytadren, crinone,deslorelin, droloxifene, dutasteride, Elimina, Laval University EM-800,Laval University EM-652, epitiostanol, epristeride, Mediolanum EP-23904,EntreMed 2-ME, exemestane, fadrozole, finasteride, formestane, Pharmacia& Upjohn FCE-24304, ganirelix, goserelin, Shire gonadorelin agonist,Glaxo Wellcome GW-5638, Hoechst Marion Roussel Hoe-766, NCI hCG,idoxifene, isocordoin, Zeneca ICI-182780, Zeneca ICI-118630, TulaneUniversity J015X, Schering Ag J96, ketanserin, lanreotide, MilkhausLDI-200, letrozol, leuprolide, leuprorelin, liarozole, lisuride hydrogenmaleate, loxiglumide, mepitiostane, Ligand Pharmaceuticals LG-1127,LG-1447, LG-2293, LG-2527, LG-2716, Bone Care International LR-103,Lilly LY-326315, Lilly LY-353381-HCl, Lilly LY-326391, Lilly LY-353381,Lilly LY-357489, miproxifene phosphate, Orion Pharma MPV-2213ad, TulaneUniversity MZ-4-71, nafarelin, nilutamide, Snow Brand NKS01, Azko NobelORG-31710, Azko Nobel ORG-31806, orimeten, orimetene, orimetine,ormeloxifene, osaterone, Smithkline Beecham SKB-105657, Tokyo UniversityOSW-1, Peptech PTL-03001, Pharmacia & Upjohn PNU-156765, quinagolide,ramorelix, Raloxifene, statin, sandostatin LAR, Shionogi S-10364,Novartis SMT-487, somavert, somatostatin, tamoxifen, tamoxifenmethiodide, teverelix, toremifene, triptorelin, TT-232, vapreotide,vorozole, Yamanouchi YM-116, Yamanouchi YM-511, Yamanouchi YM-55208,Yamanouchi YM-53789, Schering AG ZK-1911703, Schering AG ZK-230211, andZeneca ZD-182780, alpha-carotene, alpha-difluoromethyl-arginine,acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10,antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplastonAS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol,baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015,bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide,Wellcome BW-502, Wellcome BW-773, calcium carbonate, Calcet, Calci-Chew,Calci-Mix, Roxane calcium carbonate tablets, caracemide, carmethizolehydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053,Chemex CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937,Warner-Lambert CI-941, Warner-Lambert CI-958, clanfenur, claviridenone,ICN compound 1259, ICN compound 4711, Contracan, Cell Pathways CP-461,Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine,cytocytin, Merz D-609, DABIS maleate, datelliptinium, DFMO, didemnin-B,dihaematoporphyrin ether, dihydrolenperone dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel,Encore Pharmaceuticals E7869, elliprabin, elliptinium acetate, TsumuraEPMTC, ergotamine, etoposide, etretinate, Eulexin, Cell PathwaysExisulind (sulindac sulphone or CP-246), fenretinide, Florical, FujisawaFR-57704, gallium nitrate, gemcitabine, genkwadaphnin, Gerimed, ChugaiGLA-43, Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, GreenCross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine,irinotecan, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477,ketoconazole, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110,American Cyanamid L-623, leucovorin, levamisole, leukoregulin,lonidamine, Lundbeck LU-23-112, Lilly LY-186641, Materna, NCI (US) MAP,marycin, Merrel Dow MDL-27048, Medco MEDR-340, megestrol, merbarone,merocyanine derivatives, methylanilinoacridine, Molecular GeneticsMGI-136, minactivin, mitonafide, mitoquidone, Monocal, mopidamol,motretinide, Zenyaku Kogyo MST-16, Mylanta, N-(retinoyl)amino acids,Nilandron, Nisshin Flour Milling N-021, N-acylated-dehydroalanines,nafazatrom, Taisho NCU-190, Nephro-Calci tablets, nocodazole derivative,Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCINSC-95580, octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, retinoids, R-flurbiprofen(Encore Pharmaceuticals), Sandostatin, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, Scherring-Plough SC-57050, Scherring-PloughSC-57068, selenium (selenite and selenomethionine), SmithKlineSK&F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol,spirocyclopropane derivatives, spirogermanium, Unimed, SS PharmaceuticalSS-554, strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071,Sugen SU-101, Sugen SU-5416, Sugen SU-6668, sulindac, sulindac sulfone,superoxide dismutase, Toyama T-506, Toyama T-680, taxol, TeijinTEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol,Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028,ukrain, Eastman Kodak USB-006, vinblastine, vinblastine sulfate,vincristine, vincristine sulfate, vindesine, vindesine sulfate,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides,Yamanouchi YM-534, Zileuton, ursodeoxycholic acid, Zanosar.

In some embodiments, the chemotherapeutic agent comprises BacillusCalmette-Guerin (BCG).

In some embodiments, the active agent comprises an antibiotic agent. Insome embodiments, the pharmaceutical agent comprises an antibioticagent. In some embodiments, the antibiotic agent comprises at least oneof: amikacin, amoxicillin, gentamicin, kanamycin, neomycin, netilmicin,paromomycin, tobramycin, geldanamycin, herbimycin, carbacephem(loracarbef), ertapenem, doripenem, imipenem, cefadroxil, cefazolin,cefalotin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil,cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone,cefepime, ceftobiprole, clarithromycin, clavulanic acid, clindamycin,teicoplanin, azithromycin, dirithromycin, erythromycin, troleandomycin,telithromycin, aztreonam, ampicillin, azlocillin, bacampicillin,carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin,meticillin, nafcillin, norfloxacin, oxacillin, penicillin G, penicillinV, piperacillin, pvampicillin, pivmecillinam, ticarcillin, bacitracin,colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin,levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, trovafloxacin,grepafloxacin, sparfloxacin, afenide, prontosil, sulfacetamide,sulfamethizole, sulfanilimide, sulfamethoxazole, sulfisoxazole,trimethoprim, trimethoprim-sulfamethoxazole, demeclocycline,doxycycline, oxytetracycline, tetracycline, arsphenamine,chloramphenicol, lincomycin, ethambutol, fosfomycin, furazolidone,isoniazid, linezolid, mupirocin, nitrofurantoin, platensimycin,pyrazinamide, quinupristin/dalfopristin, rifampin, thiamphenicol,rifampicin, minocycline, sultamicillin, sulbactam, sulphonamides,mitomycin, spectinomycin, spiramycin, roxithromycin, and meropenem.

In some embodiments, the antibiotic agent comprises erythromycin.

In some embodiments, the active agent comprises an active biologicalagent. In some embodiments, the active biological agent comprises anactive secondary, tertiary or quaternary structure. In some embodiments,the active biological agent comprises at least one of growth factors,cytokines, peptides, proteins, enzymes, glycoproteins, nucleic acids,antisense nucleic acids, fatty acids, antimicrobials, vitamins,hormones, steroids, lipids, polysaccharides, carbohydrates, a hormone,gene therapies, RNA, siRNA, and/or cellular therapies such as stem cellsand/or T-cells.

In some embodiments, the active biological agent comprises siRNA.

In some embodiments of the methods and/or devices provided herein, thedevice further comprises a stent. In some embodiments, the substrate isnot the stent.

Methods of Manufacturing Generally

In some embodiments, a coating is formed on said substrate by a processcomprising depositing a polymer and/or the active agent by an e-RESS, ane-SEDS, or an e-DPC process. In some embodiments, the process of formingsaid coating provides improved adherence of the coating to the substrateprior to deployment of the device at the intervention site andfacilitates dissociation of said coating from said substrate at theintervention site. In some embodiments, the coating is formed on saidsubstrate by a process comprising depositing the active agent by ane-RESS, an e-SEDS, or an e-DPC process without electrically charging thesubstrate. In some embodiments, the coating is formed on said substrateby a process comprising depositing the active agent on the substrate byan e-RESS, an e-SEDS, or an e-DPC process without creating an electricalpotential between the substrate and a coating apparatus used to depositthe active agent.

Means for creating the bioabsorbable polymer(s)+drug (s) coating of thedevice with or without a substrate:

-   -   Spray coat the coating-form with drug and polymer as is done in        Micell process (e-RESS, e-DPC, compressed-gas sintering).    -   Perform multiple and sequential coating-sintering steps where        different materials may be deposited in each step, thus creating        a laminated structure with a multitude of thin layers of        drug(s), polymer(s) or drug+polymer that build the final device.    -   Perform the deposition of polymer(s)+drug(s) laminates with the        inclusion of a mask on the inner (luminal) surface of the        device. Such a mask could be as simple as a non-conductive        mandrel inserted through the internal diameter of the coating        form. This masking could take place prior to any layers being        added, or be purposefully inserted after several layers are        deposited continuously around the entire coating-form.

In some embodiments, the coating comprises a microstructure. In someembodiments, particles of the active agent are sequestered orencapsulated within said microstructure. In some embodiments, themicrostructure comprises microchannels, micropores and/or microcavities.In some embodiments, the microstructure is selected to allow sustainedrelease of the active agent. In some embodiments, the microstructure isselected to allow controlled release of the active agent.

Other methods for preparing the coating include solvent based coatingmethods and plasma based coating methods. In some embodiments, thecoating is prepared by a solvent based coating method. In someembodiments, the coating is prepared by a solvent plasma based coatingmethod.

Another advantage of the present invention is the ability to create adelivery device with a controlled (dialed-in) drug-elution profile. Viathe ability to have different materials in each layer of the laminatestructure and the ability to control the location of drug(s)independently in these layers, the method enables a device that couldrelease drugs at very specific elution profiles, programmed sequentialand/or parallel elution profiles. Also, the present invention allowscontrolled elution of one drug without affecting the elution of a seconddrug (or different doses of the same drug).

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted totransfer from the substrate to an intervention site upon stimulating thecoating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without electricallycharging the substrate, wherein forming the coating results in at leasta portion of the coating being adapted to transfer from the substrate toan intervention site upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process without creating anelectrical potential between the substrate and a coating apparatus usedin the at least one e-RESS, an e-SEDS, and an e-DPC process, whereinforming the coating results in at least a portion of the coating beingadapted to transfer from the substrate to an intervention site uponstimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to transferfrom the substrate to an intervention site upon stimulating the coatingwith a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted tofree from the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to free fromthe substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todissociate from the substrate upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to dissociatefrom the substrate upon stimulating the coating with a stimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of an e-RESS, an e-SEDS, and an e-DPC process, wherein forming thecoating results in at least a portion of the coating being adapted todeliver to the intervention site upon stimulating the coating with astimulation.

Provided herein is a method of forming a medical device comprising asubstrate and a coating on at least a portion of the substrate, whereinthe coating comprises an active agent, the method comprising: providingthe substrate; and forming the coating on at least a portion of thesubstrate by depositing the active agent by on the substrate by at leastone of a dipping and/or a spraying process, wherein forming the coatingresults in at least a portion of the coating being adapted to deliver tothe intervention site upon stimulating the coating with a stimulation.

In some embodiments, the e-RESS, the e-SEDS, and/or the e-DPC processused in forming the coating is performed without electrically chargingthe substrate. In some embodiments, the e-RESS, the e-SEDS, and/or thee-DPC process used in forming the coating is performed without creatingan electrical potential between the substrate and the coating apparatusused in the e-RESS, the e-SEDS, and/or the e-DPC process.

In some embodiments, forming the coating results in the coating adheringto the substrate prior to the substrate reaching the intervention site.

Some embodiments further comprise providing a release agent on saidsubstrate. In some embodiments, providing the release agent step isperformed prior to the forming the coating step. In some embodiments,the release agent comprises at least one of: a biocompatible releaseagent, a non-biocompatible release agent, a powder, a lubricant, asurface modification of the substrate, a viscous fluid, a gel, theactive agent, a second active agent, a physical characteristic of thesubstrate. In some embodiments, the physical characteristic of thesubstrate comprises at least one of: a patterned coating surface of thesubstrate, and a ribbed surface of the substrate. In some embodiments,the release agent comprises a property that is capable of changing atthe intervention site. In some embodiments, the property comprises aphysical property. In some embodiments, the property comprises achemical property. In some embodiments, the release agent is capable ofchanging a property when in contact with at least one of a biologictissue and a biologic fluid. In some embodiments, the release agent iscapable of changing a property when in contact with an aqueous liquid.In some embodiments, the coating results in a coating property thatfacilitates transfer of the coating to the intervention site. In someembodiments, the coating property comprises a physical characteristic ofthe coating. In some embodiments, the physical characteristic comprisesa pattern.

In some embodiments, forming the coating facilitates transfer of thecoating to the intervention site.

In some embodiments, transferring, freeing, dissociating, depositing,and/or tacking step comprises softening the polymer by hydration,degradation or by a combination of hydration and degradation. In someembodiments, the transferring, freeing, dissociating, depositing, and/ortacking step comprises softening the polymer by hydrolysis of thepolymer.

In some embodiments, the providing step comprises forming the coating bya solvent based coating method. In some embodiments, the providing stepcomprises forming the coating by a solvent plasma based method.

In some embodiments, providing the device comprises depositing aplurality of layers on said substrate to form the coating, wherein atleast one of the layers comprises the active agent. In some embodiments,at least one of the layers comprises a polymer. In some embodiments, thepolymer is bioabsorbable. In some embodiments, the active agent and thepolymer are in the same layer, in separate layers, or form overlappinglayers. In some embodiments, the plurality of layers comprise fivelayers deposited as follows: a first polymer layer, a first active agentlayer, a second polymer layer, a second active agent layer and a thirdpolymer layer.

EXAMPLES

The following examples are provided to illustrate selected embodiments.They should not be considered as limiting the scope of the invention,but merely as being illustrative and representative thereof. For eachexample listed herein, multiple analytical techniques may be provided.Any single technique of the multiple techniques listed may be sufficientto show the parameter and/or characteristic being tested, or anycombination of techniques may be used to show such parameter and/orcharacteristic. Those skilled in the art will be familiar with a widerange of analytical techniques for the characterization of drug/polymercoatings. Techniques presented here, but not limited to, may be used toadditionally and/or alternatively characterize specific properties ofthe coatings with variations and adjustments employed which would beobvious to those skilled in the art.

Sample Preparation

Generally speaking, coatings on stents, on balloons, on coupons, onother substrates, or on samples prepared for in-vivo models are preparedas herein. Nevertheless, modifications for a given analytical method arepresented within the examples shown, and/or would be obvious to onehaving skill in the art. Thus, numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from the invention. It should be understood that variousalternatives to the embodiments of the invention described herein andexamples provided may be employed in practicing the invention andshowing the parameters and/or characteristics described.

Coatings on Balloons

Coated balloons as described herein and/or made by a method disclosedherein are prepared. In some examples, the coated balloons have atargeted coating thickness of ˜15 microns (˜5 microns of active agent).In some examples, the coating process is PDPDP (Polymer, sinter, Drug,Polymer, sinter, Drug, Polymer, sinter) using deposition of drug in drypowder form and deposition of polymer particles by RESS methods andequipment described herein. In the illustrations herein, resultingcoated balloons may have a 3-layer coating comprising polymer (forexample, PLGA) in the first layer, drug (for example, rapamycin) in asecond layer and polymer in the third layer, where a portion of thethird layer is substantially drug free (e.g. a sub-layer within thethird layer having a thickness equal to a fraction of the thickness ofthe third layer). As described layer, the middle layer (or drug layer)may be overlapping with one or both first (polymer) and third (polymer)layer. The overlap between the drug layer and the polymer layers isdefined by extension of polymer material into physical space largelyoccupied by the drug. The overlap between the drug and polymer layersmay relate to partial packing of the drug particles during the formationof the drug layer. When crystal drug particles are deposited on top ofthe first polymer layer, voids and or gaps may remain between drycrystal particles. The voids and gaps are available to be occupied byparticles deposited during the formation of the third (polymer) layer.Some of the particles from the third (polymer) layer may rest in thevicinity of drug particles in the second (drug) layer. When thesintering step is completed for the third (polymer) layer, the thirdpolymer layer particles fuse to form a continuous film that forms thethird (polymer) layer. In some embodiments, the third (polymer) layerhowever will have a portion along the longitudinal axis of the stentwhereby the portion is free of contacts between polymer material anddrug particles. The portion of the third layer that is substantially ofcontact with drug particles can be as thin as 1 nanometer.

Polymer-coated balloons having coatings comprising polymer but no drugare made by a method disclosed herein and are prepared having a targetedcoating thickness of, for example, about, about 0.5, 1, 2, 3, 4, 5, 10,15, 20, 25, 30, 35, 40, 45, or 50 microns, depending in part on whetherthe coating expands upon hydration and if so whether it is hydrated. Inembodiments, the coating thickness is 1-5 microns. In other embodiments,it is 1-10 microns.

An example coating process is PPP (PLGA, sinter, PLGA, sinter, PLGA,sinter) using RESS methods and equipment described herein. Thesepolymer-coated balloons may be used as control samples in some of theexamples, infra.

In some examples, the balloons are made of a compliant polymer. In someexamples, the balloons are made of a non-compliant polymer. The balloonsmay be, in some examples, 5 to 50 mm in length, preferably 10-20 mm inlength.

Balloons can be coated while inflated, and later compacted, or they canbe coated while uninflated. If a balloon is coated while inflated andlater folded or otherwise compacted, then a portion of the coating canbe protected during insertion by virtue of being disposed within theportion of the balloon that is not exposed until inflation. The coatingcan also be protected by using a sheath or other covering, as describedin the art for facilitating insertion of an angioplasty balloon. Thecoating released from a balloon may be analyzed (for example, foranalysis of a coating band and/or coating a portion of the balloon).Alternatively, in some examples, the coating is analyzed directly on theballoon. This coating, and/or coating and balloon, may be sliced intosections which may be turned 90 degrees and visualized using the surfacecomposition techniques presented herein or other techniques known in theart for surface composition analysis (or other characteristics, such ascrystallinity, for example). In this way, what could be an analysis ofcoating composition through a depth when the coating is on the balloonor as removed from the balloon (i.e. a depth from the abluminal surfaceof the coating to the surface of the removed coating that once contactedthe balloon or a portion thereof), becomes a surface analysis of thecoating which can, for example, show the layers in the slice of coating,at much higher resolution. Residual coating on an extracted balloon alsocan be analyzed and compared to the amount of coating on an unusedballoon, using, e.g., HPLC, as noted herein. Coating removed from theballoon, or analyzed without removal and/or release from the balloon,may be treated the same way, and assayed, visualized, and/orcharacterized as presented herein using the techniques described and/orother techniques known to a person of skill in the art.

Coatings on Stents

Coated stents as described herein and/or made by a method disclosedherein are prepared. In some examples, the coated stents have a targetedthickness of ˜15 microns (˜5 microns of active agent). In some examples,the coating process is PDPDP (Polymer, sinter, Drug, Polymer, sinter,Drug, Polymer, sinter) using deposition of drug in dry powder form anddeposition of polymer particles by RESS methods and equipment describedherein. In the illustrations herein, resulting coated stents may have a3-layer coating comprising polymer (for example, PLGA) in the firstlayer, drug (for example, rapamycin) in a second layer and polymer inthe third layer, where a portion of the third layer is substantiallydrug free (e.g. a sub-layer within the third layer having a thicknessequal to a fraction of the thickness of the third layer). As described,the middle layer (or drug layer) may be overlapping with one or bothfirst (polymer) and third (polymer) layer. The overlap between the druglayer and the polymer layers is defined by extension of polymer materialinto physical space largely occupied by the drug. The overlap betweenthe drug and polymer layers may relate to partial packing of the drugparticles during the formation of the drug layer. When crystal drugparticles are deposited on top of the first polymer layer, voids and orgaps may remain between dry crystal particles. The voids and gaps areavailable to be occupied by particles deposited during the formation ofthe third (polymer) layer. Some of the particles from the third(polymer) layer may rest in the vicinity of drug particles in the second(drug) layer. When the sintering step is completed for the third(polymer) layer, the third polymer layer particles fuse to form acontinuous film that forms the third (polymer) layer. In someembodiments, the third (polymer) layer however will have a portion alongthe longitudinal axis of the stent whereby the portion is free ofcontacts between polymer material and drug particles. The portion of thethird layer that is substantially of contact with drug particles can beas thin as 1 nanometer.

Polymer-coated stents having coatings comprising polymer but no drug aremade by a method disclosed herein and are prepared having a targetedthickness of, for example, ˜5 microns. An example coating process is PPP(PLGA, sinter, PLGA, sinter, PLGA, sinter) using RESS methods andequipment described herein. These polymer-coated stents may be used ascontrol samples in some of the examples, infra.

In some examples, the stents are made of a cobalt-chromium alloy and are5 to 50 mm in length, preferably 10-20 mm in length, with struts ofthickness between 20 and 100 microns, preferably 50-70 microns,measuring from an abluminal surface to a luminal surface, or measuringfrom a side wall to a side wall. In some examples, the stent may be cutlengthwise and opened to lay flat be visualized and/or assayed using theparticular analytical technique provided.

The coating may be removed (for example, for analysis of a coating bandand/or coating on a strut, and/or coating on the abluminal surface of aflattened stent) by scraping the coating off using a scalpel, knife orother sharp tool. This coating may be sliced into sections which may beturned 90 degrees and visualized using the surface compositiontechniques presented herein or other techniques known in the art forsurface composition analysis (or other characteristics, such ascrystallinity, for example). In this way, what was an analysis ofcoating composition through a depth when the coating was on the stent oras removed from the stent (i.e. a depth from the abluminal surface ofthe coating to the surface of the removed coating that once contactedthe strut or a portion thereof), becomes a surface analysis of thecoating which can, for example, show the layers in the slice of coating,at much higher resolution. Coating removed from the stent may be treatedthe same way, and assayed, visualized, and/or characterized as presentedherein using the techniques described and/or other techniques known to aperson of skill in the art.

Coatings on Coupons

In some examples, samples comprise coupons of glass, metal, e.g.cobalt-chromium, or another substance that are prepared with coatings asdescribed herein, with a plurality of layers as described herein, and/ormade by a method disclosed herein. In some examples, the coatingscomprise polymer. In some examples, the coatings comprise polymer andactive agent. In some examples, the coated coupons are prepared having atargeted thickness of ˜10 microns (with ˜5 microns of active agent), andhave coating layers as described for the coated stent samples, infra.

Sample Preparation for In-Vivo Models

Devices comprising ballons having coatings disclosed herein are deployedin the porcine coronary arteries of pigs (domestic swine, juvenile farmpigs, or Yucatan miniature swine). Porcine coronary angioplasty isexploited herein since such model yields results that are comparable toother investigations assaying neointimal hyperplasia in human subjects.The balloons are expanded to a 1:1.1 balloon:artery ratio. At multipletime points, animals are euthanized (e.g. t=1 day, 7 days, 14 days, 21days, and 28 days), the tissue surrounding the intervention site isextracted, and assayed.

Devices comprising balloons having coatings disclosed hereinalternatively are implanted in the common iliac arteries of New Zealandwhite rabbits. The balloons are expanded to a 1:1.1 balloon:arteryratio. At multiple time points, animals are euthanized (e.g., t=1 day, 7days, 14 days, 21 days, and 28 days), the tissue surrounding theintervention site is extracted, and assayed.

Example 1 General eDPC and eRESS Deposition Methods and Coating of Stent

This example employs equipment and processes described inPCT/US2006/027321, “Polymer coatings containing drug powder ofcontrolled morphology,” (WO 2007/011707), the contents of which areherein incorporated by reference in its entirety.

A coated coronary stent is prepared as follows:

3.0×18 mm stainless steel (316 L) metal stent (Burpee MaterialsTechnology, LLC: http://www.burpeetech.com/) is cleaned prior to coatingvia ultrasonic washing followed by solvent rinse with dichloromethaneand hexane.

A drug-containing polymer coating is deposited on the stent as follows:

The metal stent serving as a target substrate for rapamycin coating isplaced in a vessel and attached to a high voltage electrode. The vessel(V), of approximately 1500 cm3 volume, is equipped with two separatenozzles through which rapamycin or polymers could be selectivelyintroduced into the vessel. Both nozzles are grounded. Additionally, thevessel (V) is equipped with a separate port is available for purging thevessel. Upstream of one nozzle (D) is a small pressure vessel (PV)approximately 5 cm3 in volume with three ports to be used as inlets andoutlets. Each port is equipped with a valve which could be actuatedopened or closed. One port, port (1) used as an inlet, is an additionport for the dry powdered rapamycin. Port (2), also an inlet is used tofeed pressurized gas, liquid, or supercritical fluid into PV. Port (3),used as an outlet, is used to connect the pressure vessel (PV) withnozzle (D) contained in the primary vessel (V) with the target coupon.

170 micrograms of rapamycin (from Chemwerth www.chemwerth.com) that isjet-milled to an average (crystalline) particle size of ˜2 microns; PLGApolymer with 50% glycolic acid content, 0.63 dL/g inherent viscosity(Durect Corp. http://www.absorbables.com/) is employed. Rapamycin isloaded into (PV) through port (1) then port (1) is actuated to theclosed position. Gaseous carbon dioxide is then added to (PV) to apressure of 400 to 600 psig at 20° C. through port (2), then port (2) isclosed to the source gas.

The second nozzle, nozzle (P), is used to feed precipitated PLGA polymerparticles into vessel (V) to coat the stainless steel stent. Nozzle (P)is equipped with a heater and controller to minimize heat loss due tothe expansion of liquefied gases. Upstream of nozzle (P) is a pressurevessel, (PV2), with approximately 25-cm3 internal volume. The pressurevessel (PV2) is equipped with multiple ports to be used for inlets,outlets, thermocouples, and pressure transducers. Additionally, (PV2) isequipped with a heater and a temperature controller. Each port isconnected to the appropriate valves, metering valves, pressureregulators, or plugs to ensure adequate control of material into and outof the pressure vessel (PV2). One outlet from (PV2) is connected to ametering valve through pressure rated tubing which is then connected tonozzle (P) located in vessel (V). The metal stent is then charged to 40kV using a Glassman Series EL high-voltage power source. The followingcoatings and sintering steps are completed:

-   -   e-RESS polymer (approx 200 micrograms),    -   sinter w/compressed gas,    -   e-DPC drug (˜85 micrograms,    -   e-RESS polymer (˜200-250 micrograms),    -   sinter w/compressed gas,    -   e-DPC drug (˜85 micrograms),    -   e-RESS polymer (˜200-300 micrograms), and    -   sinter w/compressed gas.

The process produces a three layer microlaminate construction w/170micrograms of drug, 600-750 micrograms of polymer and a total coatingthickness ˜15 microns.

Example 2 General eDPC and eRESS Deposition Methods and Coating of StentUsing a Release Agent

A coated coronary stent is prepared as described in Example 1, exceptthat prior to coating with the drug-containing polymer, a layer of PTFErelease agent is electrostatically deposited on the stent.

Example 3 Example of Coating a Substrate with No Electrocharging of theSubstrate

A coated coronary stent is prepared as described in Example 1, exceptthat the stent is not electrically charged during the coating process.

Example 4

This example illustrates embodiments that provide a coated coronarystent that frees a coating thereon by a stimulation. The stimulation inthis embodiment is expansion of the stent, which frees the coating fromthe stent, at least in part.

The embodiment comprises a nitinol stent framework over an angioplastyballoon, wherein the nitinol stent memory is set to a collapseddiameter, and the stent is expanded to a deployed diameter by inflationof the angioplasty balloon, which thereafter, upon deflation of theballoon allows the stent to return to its collapsed diameter and leavethe coating (or a portion thereof), at the intervention site. Thecoating comprises a rapamycin-polymer coating wherein at least part ofrapamycin is in crystalline form and the rapamycin-polymer coatingcomprises one or more resorbable polymers.

In these experiments two different polymers are employed:

-   -   Polymer A: −50:50 PLGA-Ester End Group, MW˜19 kD, degradation        rate ˜1-2 months    -   Polymer B: −50:50 PLGA-Carboxylate End Group, MW˜10 kD,        degradation rate ˜28 days

In certain embodiments, stents are coated as follows:

-   -   AS1: Polymer A/Rapamycin/Polymer A/Rapamycin/Polymer A    -   AS2: Polymer A/Rapamycin/Polymer A/Rapamycin/Polymer B    -   AS1 (B) or AS1(213): Polymer B/Rapamycin/Polymer        B/Rapamycin/Polymer B    -   AS1b: Polymer A/Rapamycin/Polymer A/Rapamycin/Polymer A    -   AS2b: Polymer A/Rapamycin/Polymer A/Rapamycin/Polymer B

The coated stents stent prepared as described are loaded onto a ballooncatheter. A segment of optically clear TYGON® B-44-3 Beverage Tubingwith O.D.=0.125″, I.D.=0.0625″ (available from McMaster-Carr, PartNumber: 5114K11 (www.mcmaster.com) is filled with phosphate-bufferedsaline solution and immersed in a water bath at 37° C. to mimicphysiological conditions of deployment into a coronary artery. Thecoated stents are inserted into the tubing and the catheter-balloon isinflated to 13 ATM for less than 20 seconds to deploy the stent againstthe tubing wall. Optical microscopy of the stents and of the tubing isperformed immediately after retraction of the stent delivery system toshow that some of the coating was released from the strut. Calculationsof the amount of coating left on the stent and/or freed from the stent,by means of area measurements, can determine the amount of coating thatwas freed from, transferred from, and or dissociated from the stent, andthe amount of coating that was deposited at, and/or delivered to thetubing (i.e., the intervention site).

In an alternative embodiment, the stent framework is not comprised of amemory metal, rather is plastically deformable and connected to theballoon, such that the stent shape (e.g. diameter) is defined by and/orcontrolled by the shape (e.g., diameter) of the balloon, and the stentexpands and collapses with the balloon.

Example 5

This example illustrates embodiments that provide a coated coronarystent that frees a coating thereon by a stimulation. The stimulation inthis embodiment is a combination of a mechanical stimulation and achemical stimulation.

Example 6

This example illustrates embodiments that provide a coated coronarystent that frees a coating thereon by a stimulation. The stimulation inthis embodiment is a chemical stimulation. The balloon of the stentdelivery system is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The stent (having theballoon thereunder) is positioned at the intervention site. The balloonis pressurized to at least to at least 25% below its nominal inflationpressure. Upon pressurization of the balloon in the diseased artery, atleast about 10% to at least about 30% of the coating is released intothe intervention site and upon depressurization and removal of thedevice, this material is deposited at the intervention site.

Example 7

This example illustrates embodiments that provide a coated coronarystent that frees a coating thereon by a stimulation. The stimulation inthis embodiment is a thermal stimulation.

Example 8 In-Vitro Study of Coating Freed From a Stent

One sample of the coated stent prepared as described in Example 1 wasloaded onto a balloon catheter. A segment of optically clear TYGON®B-44-3 Beverage Tubing with O.D.=0.125″, I.D.=0.0625″ (available fromMcMaster-Carr, Part Number: 5114K11 (www.mcmaster.com) was filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a coronaryartery. The coated stent was inserted into the tubing and thecatheter-balloon was inflated to 13 ATM to deploy the stent against thetubing wall. Optical microscopy was performed immediately afterdeployment, where it was clear that some of the coating was releasedfrom the strut.

Example 9 In-Vitro Study of Coating Freed from a Stent Using a ReleaseAgent

One sample of the coated stent was prepared as described in Example 2,using about 700 micrograms polymer and 160 micrograms API, an AS1formulation (PsDPsDPs), and sintered at 25 psig and 75° C. for 10minutes, was loaded onto a balloon catheter. The stent was pre-wetted byimmersion in an isotonic saline bath at 37° C. for 3 minutes. A segmentof optically clear TYGON® B-44-3 Beverage Tubing with O.D.=0.125″,I.D.=0.0625″ (available from McMaster-Carr Part Number 5114K11;www.mcmaster.com) was filled with phosphate-buffered saline solution andimmersed in a water bath at 37° C. to mimic physiological conditions ofdeployment into a coronary artery. The coated stent was inserted intothe tubing and the catheter-balloon was inflated to 13 ATM to deploy thestent against the tubing wall. Optical microscopy was performedimmediately after deployment and showed that some of the coating hasbeen released from the strut.

Example 10 In Vivo Studies of Coating Transfer from a Stent

Another sample of the coated stent was prepared for in vivo evaluationin a porcine coronary artery model using the Yucatan pig. Subjects wereinitially given 650 mg acetylsalicylic acid and 300 mg Plavix.Maintenance doses of 81 mg acetylsalicylic acid and 75 mg Plavix wereadministered. The target ACT (activated clotting time) for the procedurewas about 250 seconds. Stent oversizing in relation to the artery wasabout 10-20%. The preparation of the sirolimus-coated stent was the sameas described in Example 1 and used for the in vitro deployment intotubing, except that the device was sterilized using ETO prior toimplantation into the animal. The histology of the stented artery after28 days showed evidence of the extrusion and bulk-migration of thecoating into the surrounding arterial tissue. This extrusion providestreatment of ˜2.5× greater arterial tissue (area) vs. the abluminal areaof the strut itself.

The bulk concentration of drug was measured in the arterial tissuesurrounding the implanted stent at 1, 3, 7, 14, and 28 days afterimplant, and provided a quantitative measure of the high efficiency oftransfer of drug into the therapeutic site using devices and methods ofthe invention. The amount of drug that was detected in the arterialtissue was as follows: 1 day after implant, ˜6 μg; 3 days after implant,˜16 μg; 7 days after implant, ˜30 μg; 14 days after implant, ˜30 μg; 28days after implant, ˜13 μg. Peak tissue concentration of sirolimus of˜30 μg at 14 days after implant was representative of approximately⅙^(th) of the total drug that had been loaded on the stent. Note thatsome drug likely metabolized or diffused out of the arterial tissue intoother areas of the body. These results demonstrate the effectiveness ofthe devices and methods of the invention relative to other systems,wherein transfer of the coating via bulk migration is inhibited bypermanent and/or hard polymers, typically showing 1 to 5% the level ofefficiency of drug transfer shown here.

Example 11 Stent Examples

In one experiment, a coated coronary stent is prepared as follows.3.0×16 mm Co—Cr alloy metal stent (Skylor stent from Invatec(www.invatec.com)) is coated with a drug-containing coating (170micrograms of rapamycin from Chemwerth www.chemwerth.com that isjet-milled to an average (crystalline) particle size of ˜2 microns; PLGApolymer with 50% glycolic acid content, 0.63 dL/g inherent viscosity(Durect Corp. http://www.absorbables.com/).

Equipment and process similar to those employed in Example 1 are used.

The following coating and sintering steps are carried out:

-   -   e-RESS polymer (approx 100 micrograms),    -   sinter w/compressed gas,    -   e-DPC drug (˜35 micrograms,    -   e-RESS polymer (˜100-150 micrograms),    -   sinter w/compressed gas,    -   e-DPC drug (˜35 micrograms),    -   e-RESS polymer (˜100-200 micrograms), and    -   sinter w/compressed gas

The process produces a coated stent with a ‘three layer microlaminateconstruction w/˜70 micrograms of drug, 300-375 micrograms of polymer anda total coating thickness of 6-8 microns. Upon deployment, 1/10th of thecoating is freed from the stent and delivered to the arterial tissue.

In another experiment, a coated coronary stent is prepared as follows.3.0×16 mm Co—Cr alloy metal stent (Skylor stent from Invatec(www.invatec.com)) is coated with a drug-containing coating by spraycoating from a solution of PLGA polymer (Mw˜30 kg/mol from Durect Corp)and sirolimus (from Chemwerth www.chemwerth.com).

Equipment and process similar to those employed in Example 4 are used.

Resulting in a coating of ˜8 μm thickness, containing 70 μg ofsirolimus.

Upon deployment, ⅕th of the coating is extruded from the stent at theintervention site (e.g., the arterial tissue.)

Example 12 Cutting Balloons Cutting Balloon (1)—Mechanical Stimulationto Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. Upon deflation and removal of the cutting balloon from theintervention site, at least about 5% to at least about 30% of thecoating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 1 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of ˜2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon, at least about 75% ofthe coating is transferred from the device to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. A serum sample as well as a tissuesample from the deployment site is collected.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to show improvement and/ortreatment of a disease and/or ailment, for example, by testing highsensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-1β (IL-1β), and/or monocyte chemoattractant protein-1(MCP-1). The release kinetics of the drug may be shown by plotting thesirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (2) Mechanical Stimulation to Free the Coating

A cutting balloon is coated using a solution-based system (spray or dipcoating) comprising a polymer and an active agent. The coated cuttingballoon is positioned at the intervention site. The balloon is inflatedto at least 25% below its nominal inflation pressure. At least about 5%to at least about 30% of the coating is freed from the surface of thecutting balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process using a spray and/or dip coating processis employed. The intervention site is a vascular lumen wall. Uponinflation of the cutting balloon, at least about 50% of the coating isfreed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and coatingprocess using a spray and/or dip coating process is employed. Theintervention site is a coronary artery. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process using a sprayand/or dip coating process is employed. The intervention site is acavity resulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is anangioplasty catheter and the substrate is the balloon of the catheter)may be used to determine the percent of coating freed, dissociated,and/or transferred from the device. In some instances, an assessment ofthe device following the procedure alone is sufficient to assess theamount freed or dissociated from the substrate, without determination ofthe amount delivered to the intervention site. Additionally, where adetermination of improvement and/or disease treatment is desired, levelsof proinflammatory markers could be tested to show improvement and/ortreatment of a disease and/or ailment, for example, by testing highsensitive C-reactive protein (hsCRP), interleukin-6 (IL-6),interleukin-1β (IL-1β), and/or monocyte chemoattractant protein-1(MCP-1). The release kinetics of the drug may be shown by plotting thesirolimus concentrations at the timepoints noted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in using spray and/ordip coating process is secured to a balloon catheter. A segment ofoptically clear TYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″(Available from McMaster-Carr Part Number: 5114K11 (www.mcmaster.com))is filled with phosphate-buffered saline solution and immersed in awater bath at 37° C. to mimic physiological conditions of deploymentinto a subject. The coated balloon is inserted into the tubing and theballoon is inflated to at least 25% below the balloon's nominal pressureto mechanically transfer the coating from the balloon to the tubingwall. The balloon is deflated and removed from the tubing. Opticalmicroscopy is performed on the tubing and/or the balloon (which isinflated to at least 25% below the balloon's nominal pressure, at least)to determine the presence and amount of coating transferred to thetubing and/or the amount of coating freed, dissociated, and/ortransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (3) Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a release agent, a polymer and anactive agent. The coated cutting balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. At least about 5% to at least about 50% ofthe coating is freed from the surface of the cutting balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 2 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 2 is employed. The intervention site is a coronaryartery. The release agent is ePTFE powder. Upon inflation of the cuttingballoon, about 5% to about 15% of the coating is freed from the deviceresulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example2 is employed. The release agent a micronized active agent or anotheractive agent in a micronized form. The intervention site is a cavityresulting from removal of a tumor. Upon inflation of the cuttingballoon, at least about 75% of the coating is transferred from from thedevice to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is an angioplasty catheter and the substrate is theballoon of the catheter) may be used to determine the percent of coatingfreed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in Example 2 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingtransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (4) Mechanical Stimulation to Free the Coating

A cutting balloon is coated comprising a polymer and an active agent.The coated cutting balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. At least about 10% to at least about 50% of the coating isfreed from the surface of the cutting balloon and is deposited at theintervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 3 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 3 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon, about 5% to about 15% ofthe coating is freed from the device resulting in delivery of ˜2.0 μg ofdrug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example3 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon, at least about 75% ofthe coating is transferred from the device to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is acutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in Example 3 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (5) Mechanical and Chemical Stimulation to Free theCoating

A cutting balloon is coated with a formulation comprising a base layerof methyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated cuttingballoon is positioned at the intervention site. The balloon ispressurized to at least to at least 25% below its nominal inflationpressure. Upon pressurization of the cutting balloon in the diseasedartery, at least about 10% to at least about 30% of the coating isreleased into the intervention site and upon depressurization andremoval of the device, this material is deposited at the interventionsite.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon.

In one example, a base layer of methyl acrylate-methacrylic acidcopolymer is formed and additional layers of the coating is 50:50PLGA-Ester End Group, MW˜19 kD, degradation rate ˜1-2 months or 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate ˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The intervention site isa vascular lumen wall. Upon inflation of the cutting balloon, at leastabout 50% of the coating is freed from the device at the interventionsite.

In another example, a cutting balloon is coated with a base layer ofmethyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+sirolimus with total loading of sirolimus ˜20μ. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. The balloon is constructed of a semipermable polymer.The pressurization medium is pH 8 phosphate buffer. Upon inflation ofthe cutting balloon, about 5% to about 15% of the coating is freed fromthe device resulting in delivery of ˜2.0 μg of drug delivered to theartery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon, at least about 75% ofthe coating is transferred from the device to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is ancutting angioplasty catheter and the substrate is the cutting balloon ofthe catheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (6) Chemical Stimulation to Free the Coating

A cutting balloon is coated with a formulation comprising a base layerof methyl acrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated cuttingballoon is positioned at the intervention site. The balloon ispressurized to at least to at least 25% below its nominal inflationpressure. Upon pressurization of the cutting balloon in the diseasedartery, at least about 10% to at least about 30% of the coating isreleased into the intervention site and upon depressurization andremoval of the device, this material is deposited at the interventionsite. In-vivo and/or in-vitro testing as described herein may be used toanalyze the coating, the drug, the device, the intervention site and/orproperties thereof.

Cutting Balloon (7) Thermal Stimulation to Free the Coating

A cutting balloon is coated according to a method described herein andthe balloon comprises a thermoreversible polymer Pluronic F127 and anactive agent. The coated cutting balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the cuttingballoon from the intervention site, at least about 5% to at least about30% of the coating is freed from the surface of the cutting balloon andis deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the active agent is a pharmaceutical agent such as amacrolide immunosuppressive drug. Equipment and coating process similarto Example 1 is employed. The intervention site is a vascular lumenwall. Upon inflation of the cutting balloon, at least about 50% of thecoating is freed from the device at the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of PluronicF127 and sirolimus with total loading of sirolimus ˜20 μg. The device isplaced at a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, 28 days, 42days and 56 days post deployment.

The tissue and serum samples may be subjected to analysis for sirolimusconcentration. In order to determine the amount of coating freed fromthe device and/or delivered to the intervention site as a percent of thetotal amount of coating on the substrate, the tissue concentration ofsirolimus at the one hour time point (or any time point within the firstday following of the procedure) may be used along with the total contentexpected for the coating (based on the total content for themanufacturing lot) or along with the content of coating remaining on thedevice once removed and the percentage calculated. This percentage iscorrelative of the percent of coating freed, dissociated, and/ortransferred from the device and delivered to the intervention site.Alternatively, the tissue may be analyzed by various means (notedherein, including but not limited to SEM, TEM, and, where image enhancedpolymers are used, various imaging means capable of detecting theseenhanced polymers) to detect the percent of the coating freed,dissociated and/or transferred from the substrate and delivered to theintervention site. Again, the amount of coating known to be on thesubstrate based on manufacturing lot characteristics, and/or anassessment of the coating remaining on the device following removal ofthe device from the subject (for example, wherein the device is acutting angioplasty catheter and the substrate is the balloon of thecatheter) may be used to determine the percent of coating freed,dissociated, and/or transferred from the device. In some instances, anassessment of the device following the procedure alone is sufficient toassess the amount freed or dissociated from the substrate, withoutdetermination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared as in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingtransferred from the balloon. Other in-vitro tests described herein maybe used instead of this test and/or in addition to this test, adjustedfor the particularities of this device, as would be known to one ofordinary skill in the art.

Cutting Balloon (8) Sonic Stimulation to Free the Coating

A cutting balloon is coated according to a method as described hereinand the device comprises a polymer and an active agent. The coatedcutting balloon is positioned at the intervention site. The balloon isinflated to at least 25% below its nominal inflation pressure andsubjected to ultrasonic stimulation. Upon deflation and removal of thecutting balloon from the intervention site, at least about 5% to atleast about 30% of the coating is freed from the surface of the cuttingballoon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected by ultrasonicstimulation to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected by ultrasonicstimulation.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon and initiation of ultrasonic stimulation, at least about50% of the coating is freed from the device at the intervention site.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 1 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon and initiation ofultrasonic stimulation, about 5% to about 15% of the coating is freedfrom the device resulting in delivery of ˜2.0 μg of drug delivered tothe artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon and initiation ofultrasonic stimulation, at least about 75% of the coating is transferredfrom the device to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, ˜28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is a cutting angioplasty catheter and the substrateis the balloon of the catheter) may be used to determine the percent ofcoating freed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a ultrasonic waterbath at 37° C. to mimic physiological conditions of deployment into asubject. The coated balloon is inserted into the tubing and the balloonis inflated to at least 25% below the balloon's nominal pressure andultrasonic stimulation is iniatiated to mechanically transfer thecoating from the balloon to the tubing wall. The balloon is deflated andremoved from the tubing. Optical microscopy is performed on the tubingand/or the balloon (which is inflated to at least 25% below theballoon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon. Other in-vitrotests described herein may be used instead of this test and/or inaddition to this test, adjusted for the particularities of this device,as would be known to one of ordinary skill in the art.

Cutting Balloon (9) Electromagnetic Stimulation to Free the Coating

A cutting balloon is coated according to a method as described hereinand the device comprises a polymer and an active agent. The coatedcutting balloon is positioned at the intervention site. The balloon isinflated to at least 25% below its nominal inflation pressure andsubjected to electromagnetic stimulation. Upon deflation and removal ofthe cutting balloon from the intervention site, at least about 5% to atleast about 30% of the coating is freed from the surface of the cuttingballoon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected byelectromagnetic stimulation to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected byelectromagnetic stimulation.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecutting balloon and initiation of electromagnetic stimulation, at leastabout 50% of the coating is freed from the device at the interventionsite.

In another example, a cutting balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the cutting balloon. Equipment and processsimilar to Example 1 is employed. The intervention site is a coronaryartery. Upon inflation of the cutting balloon and initiation ofelectromagnetic stimulation, about 5% to about 15% of the coating isfreed from the device resulting in delivery of ˜2.0 μg of drug deliveredto the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the cutting balloon and initiation ofelectromagnetic stimulation, at least about 75% of the coating istransferred from the device to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a cutting balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, ˜28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is a cutting angioplasty catheter and the substrateis the balloon of the catheter) may be used to determine the percent ofcoating freed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

Other in-vivo tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

In-Vitro Testing:

One sample of the coated cutting balloon prepared in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure and electromagneticstimulation is initiated to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. Optical microscopy is performed on the tubing and/or the balloon(which is inflated to at least 25% below the balloon's nominal pressure,at least) to determine the presence and amount of coating transferred tothe tubing and/or the amount of coating transferred from the balloon.Other in-vitro tests described herein may be used instead of this testand/or in addition to this test, adjusted for the particularities ofthis device, as would be known to one of ordinary skill in the art.

Example 13 Drug-Delivery Balloon Catheters

Drug-Delivery Balloon (1)—Compliant Balloon

A compliant balloon is coated with a material comprising a polymer andan active agent. The coated compliant balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the compliantballoon from the intervention site, at least about 5% to at least about30% of the coating is freed from the surface of the compliant balloonand is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thecompliant balloon, at least about 50% of the coating is freed from thedevice at the intervention site.

In another example, a compliant balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the compliant balloon, about 5% toabout 15% of the coating is freed from the device resulting in deliveryof ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the compliant balloon, at least about 75%of the coating is transferred from the device to the intervention site.

In-Vivo Testing:

A group of 27 New Zealand white rabbits is prepared for a Seldingerprocedure using a compliant balloon coated with a formulation of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsirolimus with total loading of sirolimus ˜20 μg. The device is placedat a coronary artery intervention site with the assistance offluoroscopy to aid in positioning the device at the same location ineach subject. Six animals are subjected to the procedure using a coatedballoon that does not have sirolimus in the coating. After deploymentand removal of the device, 3 control animals are sacrificed at 1 hourpost deployment and serum and tissue samples are collected. The 3remaining control animals are sacrificed at 56 days post deployment.During the course of the study, serum samples are collected from controland drug-treated animals every five days. The drug treated animals, 3each, are sacrificed at 1 hour, 24 hours, 7 days, 14 days, ˜28 days, 42days and 56 days post deployment. The tissue and serum samples may besubjected to analysis for sirolimus concentration.

In order to determine the amount of coating freed from the device and/ordelivered to the intervention site as a percent of the total amount ofcoating on the substrate, the tissue concentration of sirolimus at theone hour time point (or any time point within the first day following ofthe procedure) may be used along with the total content expected for thecoating (based on the total content for the manufacturing lot) or alongwith the content of coating remaining on the device once removed and thepercentage calculated. This percentage is correlative of the percent ofcoating freed, dissociated, and/or transferred from the device anddelivered to the intervention site. Alternatively, the tissue may beanalyzed by various means (noted herein, including but not limited toSEM, TEM, and, where image enhanced polymers are used, various imagingmeans capable of detecting these enhanced polymers) to detect thepercent of the coating freed, dissociated and/or transferred from thesubstrate and delivered to the intervention site. Again, the amount ofcoating known to be on the substrate based on manufacturing lotcharacteristics, and/or an assessment of the coating remaining on thedevice following removal of the device from the subject (for example,wherein the device is a cutting angioplasty catheter and the substrateis the balloon of the catheter) may be used to determine the percent ofcoating freed, dissociated, and/or transferred from the device. In someinstances, an assessment of the device following the procedure alone issufficient to assess the amount freed or dissociated from the substrate,without determination of the amount delivered to the intervention site.Additionally, where a determination of improvement and/or diseasetreatment is desired, levels of proinflammatory markers could be testedto show improvement and/or treatment of a disease and/or ailment, forexample, by testing high sensitive C-reactive protein (hsCRP),interleukin-6 (IL-6), interleukin-1β (IL-1β), and/or monocytechemoattractant protein-1 (MCP-1). The release kinetics of the drug maybe shown by plotting the sirolimus concentrations at the timepointsnoted above.

For embodiments using different drugs other than sirolimus, thebiomarkers are selected based on the disease to be treated and the drugsadministered during the course of therapy as determined by one of skillin the art. These biomarkers may be used to show the treatment resultsfor each subject.

In-Vitro Testing:

One sample of the coated compliant balloon prepared in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Optical microscopy is performed onthe tubing and/or the balloon (which is inflated to at least 25% belowthe balloon's nominal pressure, at least) to determine the presence andamount of coating transferred to the tubing and/or the amount of coatingfreed, dissociated, and/or transferred from the balloon.

Method for the Determination of Sirolimus Levels:

Media may be assayed for sirolimus content using HPLC. Calibrationstandards containing known amounts of drug are to determine the amountof drug eluted. The multiple peaks present for the sirolimus (alsopresent in the calibration standards) are added to give the amount ofdrug eluted at that time period (in absolute amount and as a cumulativeamount eluted). HPLC analysis is performed using Waters HPLC system, setup and run on each sample as provided in the Table 1 below using aninjection volume of 100 L.

TABLE 1 Time point % Ammonium Acetate Flow Rate (minutes) % Acetonitrile(0.5%), pH 7.4 (mL/min) 0.00 10 90 1.2 1.00 10 90 1.2 12.5 95 5 1.2 13.5100 0 1.2 14.0 100 0 3 16.0 100 0 3 17.0 10 90 2 20.0 10 90 0

In-Vitro Mass Loss Test:

One sample of the coated compliant balloon prepared in Example 1 isweighed on a microbalance and then secured to a balloon catheter. Asegment of optically clear TYGON® B-44-3 tubing with O.D.=0.125″,I.D.=0.0625″ (Available from McMaster-Carr Part Number: 5114K11(www.mcmaster.com)) is filled with phosphate-buffered saline solutionand immersed in a water bath at 37° C. to mimic physiological conditionsof deployment into a subject. The coated balloon is inserted into thetubing and the balloon is inflated to at least 25% below the balloon'snominal pressure to mechanically transfer the coating from the balloonto the tubing wall. The balloon is deflated and removed from the tubing.After drying, the balloon is removed from the guidewire, further driedand weighed on a microbalance. Comparison of the pre- andpost-deployment weights indicates how much coating is freed,dissociated, and/or transferred from the balloon. This analysis mayinstead and/or alternatively include testing of the tubing to determinethe amount of coating freed, dissociated, and/or transferred from thedevice during this in-vitro test.

In-Vitro Coating Test:

One sample of the coated compliant balloon prepared in Example 1 issecured to a balloon catheter. A segment of optically clear TYGON®B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. The section of tubing exposed tothe deployed balloon is cut away from the remainder of the tubing andthe interior of the excised tubing rinsed with a small amount of ethanoland an amount of methylene chloride to make up 25 mL total volume ofrinsings which are collected in a flask for analysis. Analysis by HPLCas described above is performed to determine the amount of materialfreed, dissociated, and/or transferred from the balloon. This analysismay instead and/or alternatively include testing of the substrate itselfto determine the amount of coating freed, dissociated, and/ortransferred from the device during this in-vitro test.

In-Vitro Testing:

One sample of the coated compliant balloon prepared in Example 1 issecured to a balloon catheter. A segment of resected coronary arteryfrom Yucatan miniature swine is positionally fixed and filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the artery and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the arterial wall. The balloonis deflated and removed from the artery. The section of artery exposedto the deployed balloon is cut away from the remainder of the arterysection, placed into a tissue homogonizer and the homogenized materialis extracted with methylene chloride to make up 25 mL total volume ofrinsings which are collected in a flask for analysis. Analysis by HPLCas described above is performed to determine the amount of materialfreed, dissociated, and/or transferred from the balloon. This analysismay instead and/or alternatively include testing of the substrate itselfto determine the amount of coating freed, dissociated, and/ortransferred from the device during this in-vitro test.

For embodiments related to non-vascular or non-lumenal applications,e.g. a tumor site or other cavity or a cannulized site, the sametechnique is employed with the modification that the tissue to beassayed is resected from the tissue adjoining cavity receiving drugtreatment.

In-Vitro Testing:

One sample of the coated compliant balloon prepared in Example 1 issecured to a balloon catheter. A segment of resected coronary arteryfrom Yucatan miniature swine is positionally fixed and filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the artery and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the arterial wall. The balloonis deflated and removed from the artery. The section of artery exposedto the deployed balloon is cut away from the remainder of the arterysection and incised lengthwise to lay open the artery. Opticalmicroscopy is performed on the interior of artery to determine thepresence and amount of coating transferred to the artery and/or theamount of coating transferred from the balloon. The tissue sample isalso subjected to TEM-SEM analysis.

In-Vitro Testing of Release Kinetics:

One sample of the coated compliant balloon with total loading ofsirolimus ˜20 μg prepared in Example 1 is secured to a balloon catheter.A flask containing exactly 25 mL of pH 7.4 aqueous phosphate bufferequilibrated to 37° C. equipped for magnetic stirring is prepared. Intothis flask is placed the coated balloon and the catheter portion of theapparatus is secured such that the balloon does not touch the sides ofthe flask. The balloon is inflated to 120 psi with sterile water.Aliquots of 100 L are removed prior to addition of the balloon, afterplacement of the balloon but prior to inflation of the balloon, and atregular time intervals of 2, 4, 6, 8, 10, 12, and 14 minutes. Uponremoval of each aliquot an equivalent volume of aqueous buffer is addedto maintain the volume at 25 mL. The aliquots are analyzed by HPLC asdescribed above for the concentration of sirolimus.

In-Vitro Testing for Distal Flow Particulates:

One sample of the coated compliant balloon prepared in Example 1 issecured to a guidewire incorporating a porous filter of 100 m pore size,such as the Cordis AngioGuard emboli capture guidewire. A segment ofoptically clear TYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″(Available from McMaster-Carr Part Number: 5114K11 (www.mcmaster.com))is filled with phosphate-buffered saline solution and immersed in awater bath at 37° C. to mimic physiological conditions of deploymentinto a subject. The coated balloon is inserted into the tubing, theproximal end of the tubing surrounding the guidewire sealed with epoxy,and a hypodermic needle which is attached to an infusion pump andreservoir of 37° C. phosphate-buffered saline solution is inserted intothe tubing proximal to the balloon assembly. The flow of saline iscommenced, the distal filter is deployed and the balloon is inflated toat least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. The filter is deployed for 5minutes after removal of the balloon, the flow of saline is halted, thetubing cut adjacent to the epoxy seal, the filter retracted and removedfrom the tubing. The content of the filter is analyzed.

In-Vitro Testing for Distal Flow Particulates:

One sample of the coated compliant balloon prepared in Example 1 issecured to a guidewire. A segment of optically clear TYGON® B-44-3tubing with O.D.=0.125″, I.D.=0.0625″ (Available from McMaster-Carr PartNumber: 5114K11 (www.mcmaster.com)) is filled with phosphate-bufferedsaline solution and immersed in a water bath at 37° C. to mimicphysiological conditions of deployment into a subject and the distal endof the tubing is connected to a turbidity light scattering detector asdescribed in Analytical Ultracentrifugation of Polymers andNanoparticles, W. Machtle and L. Borger, (Springer) 2006, p. 41. Thecoated balloon is inserted into the proximal end of the tubing, theproximal end of the tubing surrounding the guidewire sealed with epoxy,and a hypodermic needle which is attached to an infusion pump andreservoir of 37° C. phosphate-buffered saline solution is inserted intothe tubing proximal to the balloon assembly. The flow of saline iscommenced, a baseline for light transmission through the detector isestablished and the balloon is inflated to at least 25% below theballoon's nominal pressure to mechanically transfer the coating from theballoon to the tubing wall. The balloon is deflated and removed from thetubing. The flow is maintained for 10 minutes after removal of theballoon, and the flow is analyzed for the presence of particles based ondetector response.

Drug-Delivery Balloon (2)—Non-Compliant Balloon

A non-compliant balloon is coated with a material comprising a polymerand an active agent. The coated non-compliant balloon is positioned atthe intervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of thenon-compliant balloon from the intervention site, at least about 5% toat least about 30% of the coating is freed from the surface of thenon-compliant balloon and is deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of thenon-compliant balloon, at least about 50% of the coating is freed fromthe device at the intervention site.

In another example, a non-compliant balloon is coated with a formulationof PLGA+sirolimus with total loading of sirolimus ˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. Upon inflation of the non-compliant balloon, about 5%to about 15% of the coating is freed from the device resulting indelivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the non-compliant balloon, at least about75% of the coating is transferred from the device to the interventionsite.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Drug-Delivery Balloon (3)—Mechanical and Chemical Stimulus

A balloon is coated with a formulation comprising a base layer of methylacrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated balloon ispositioned at the intervention site. The balloon is pressurized to atleast to at least 25% below its nominal inflation pressure. Uponpressurization of the balloon in the diseased artery, at least about 10%to at least about 30% of the coating is released into the interventionsite and upon depressurization and removal of the device, this materialis deposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment the pH mediated releaseof the coating from the balloon.

In one example, a base layer of methyl acrylate-methacrylic acidcopolymer is formed and additional layers of the coating is 50:50PLGA-Ester End Group, MW˜19 kD, degradation rate ˜1-2 months or 50:50PLGA-Carboxylate End Group, MW˜10 kD, degradation rate ˜28 days. Theactive agent is a pharmaceutical agent such as a macrolideimmunosuppressive drug. Equipment and coating process similar to Example1 is employed. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The intervention site isa vascular lumen wall. Upon inflation of the balloon, at least about 50%of the coating is freed from the device at the intervention site.

In another example, a balloon is coated with a base layer of methylacrylate-methacrylic acid copolymer and additional layers ofPLGA+sirolimus with total loading of sirolimus ˜20 μg. Equipment andprocess similar to Example 1 is employed. The intervention site is acoronary artery. The balloon is constructed of a semipermable polymer.The pressurization medium is pH 8 phosphate buffer. Upon inflation ofthe balloon, about 5% to about 15% of the coating is freed from thedevice resulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the balloon, at least about 75% of thecoating is transferred from the device to the intervention site.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Drug-Delivery Balloon (4)—Chemical Stimulus

A balloon is coated with a formulation comprising a base layer of methylacrylate-methacrylic acid copolymer and additional layers ofPLGA+paclitaxel with total dose of paclitaxel approx. 0.5 μg/mm2 of thewire. The coating and sintering process is similar to that as describedin Example 1. The balloon is constructed of a semipermable polymer. Thepressurization medium is pH 8 phosphate buffer. The coated balloon ispositioned at the intervention site. The balloon is pressurized to atleast to at least 25% below its nominal inflation pressure. Uponpressurization of the balloon in the diseased artery, at least about 10%to at least about 30% of the coating is released into the interventionsite and upon depressurization and removal of the device, this materialis deposited at the intervention site. In-vivo and/or in-vitro testingmay be performed according to the methods described herein.

Drug-Delivery Balloon (5)—Thermal Stimulus

A balloon is coated comprising a thermoreversible polymer Pluronic F127and an active agent. The coated balloon is positioned at theintervention site. The balloon is inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the balloonfrom the intervention site, at least about 5% to at least about 30% ofthe coating is freed from the surface of the balloon and is deposited atthe intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon to the interventionsite.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon.

In one example, the active agent is a pharmaceutical agent such as amacrolide immunosuppressive drug. Equipment and coating process similarto Example 1 is employed. The intervention site is a vascular lumenwall. Upon inflation of the balloon, at least about 50% of the coatingis freed from the device at the intervention site.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Drug-Delivery Balloon (6)—Sonic Stimulus

A balloon is coated with a material comprising a polymer and an activeagent. The coated balloon is positioned at the intervention site. Theballoon is inflated to at least 25% below its nominal inflation pressureand subjected to ultrasonic stimulation. Upon deflation and removal ofthe balloon from the intervention site, at least about 5% to at leastabout 30% of the coating is freed from the surface of the balloon and isdeposited at the intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected by ultrasonicstimulation to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected by ultrasonicstimulation.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of theballoon and initiation of ultrasonic stimulation, at least about 50% ofthe coating is freed from the device at the intervention site.

In another example, a balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the balloon. Equipment and process similarto Example 1 is employed. The intervention site is a coronary artery.Upon inflation of the balloon and initiation of ultrasonic stimulation,about 5% to about 15% of the coating is freed from the device resultingin delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the balloon and initiation of ultrasonicstimulation, at least about 75% of the coating is transferred from thedevice to the intervention site.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Drug-Delivery Balloon (7)—Electromagnetic Stimulus

A balloon is coated comprising a polymer and an active agent. The coatedballoon is positioned at the intervention site. The balloon is inflatedto at least 25% below its nominal inflation pressure and subjected toelectromagnetic stimulation. Upon deflation and removal of the balloonfrom the intervention site, at least about 5% to at least about 30% ofthe coating is freed from the surface of the balloon and is deposited atthe intervention site.

In some examples, the balloon unfolds during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected byelectromagnetic stimulation to the intervention site.

In some examples, the balloon twists during inflation, causingmechanical shearing forces to at least augment transfer and/or freeingand/or deposition of the coating from the balloon effected byelectromagnetic stimulation.

In one example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is apharmaceutical agent such as a macrolide immunosuppressive drug.Equipment and coating process similar to Example 1 is employed. Theintervention site is a vascular lumen wall. Upon inflation of theballoon and initiation of electromagnetic stimulation, at least about50% of the coating is freed from the device at the intervention site.

In another example, a balloon is coated with a formulation ofPLGA+sirolimus with total loading of sirolimus ˜20 μg with the coatingpreferentially on the wire of the balloon. Equipment and process similarto Example 1 is employed. The intervention site is a coronary artery.Upon inflation of the balloon and initiation of electromagneticstimulation, about 5% to about 15% of the coating is freed from thedevice resulting in delivery of ˜2.0 μg of drug delivered to the artery.

In another example, the polymer of the coating is 50:50 PLGA-Ester EndGroup, MW˜19 kD, degradation rate ˜1-2 months or 50:50 PLGA-CarboxylateEnd Group, MW˜10 kD, degradation rate ˜28 days. The active agent is achemotherapeutic agent. Equipment and coating process similar to Example1 is employed. The intervention site is a cavity resulting from removalof a tumor. Upon inflation of the balloon and initiation ofelectromagnetic stimulation, at least about 75% of the coating istransferred from the device to the intervention site.

In-vivo and/or in-vitro testing may be performed according to themethods described herein.

Drug-Delivery Balloon (8)—Electrostatically Applied Drug Release Layer

A 5×40 mm polyethylene terephthalate (PET) balloon was airbrushed withrapamycin (˜5.8 mg from rapamycin/acetone solution) as a release agent,then airbrushed with PLGA (˜1 mg) and sintered at 67° C. under vacuumfor 1 hour. The balloon was deflated, inserted in the lumen of 3/16″Tygon tubing, and pressurized to ˜245 psig at 37° C. (2 minutesequilibration time; 1 minute pressurization). Substantial transfer ofthe coating (a thick layer) to the tubing was observed. A thin layer ofcoating remained on the balloon.

In a related experiment, a 5×40 mm polyethylene terephthalate (PET)balloon was electrostatically coated with 240 micrograms of rapamycin asa release agent, then coated with PLGA (1.24 mg) by eRESS and sinteredat 68° C. for 1 hour. The balloon was deflated, inserted in the lumen of3/16″ Tygon tubing, and pressurized to 250 psig at 37° C. (2 minutesequilibration time; 1 minute pressurization). Under these conditions, notransfer of the PLGA coating to the tubing was observed.

Example 14 Balloon Delivery of Weakly Binding Drugs

A compliant balloon was electrostatically coated with a weakly bindingdrug, cyrstalline sirolimus with a nominal particle size of 2.4 microns,as part of a bioabsorbable polymer matrix in dry powder form, and thecoating sintered at low temperature. Upon introduction of the coatedballoon into a model lumen (made from Tygon tubing, as described herein)and subsequent inflation, the drug coating was shown by cross-sectionalanalysis to have transferred to the interior of the lumen. This resultshows that dry processing that isolates a weakly binding drug asparticles within a bioabsorbable polymer matrix can provide the abilityto control the delivery of weakly binding drugs.

Example 15 Drug-Delivery Balloons for Treatment of the Vasculature

Drug-Delivery Balloon (1)—Treatment of Restenosis with Paclitaxel orSirolimus

A balloon is used to prevent and/or treat restenosis in an artery. Aballoon is coated as described herein with 50:50 PLGA-Ester End Group(MW˜19 kD, degradation rate ˜1-2 months) and paclitaxel or at a loadingof 1 g/mm² or sirolimus at a loading of 5 g/mm². The coated balloon ispositioned at the arterial intervention site. The balloon is inflated toat least 25% below its nominal inflation pressure. The balloon isdeflated and removed from the intervention site, allowing the coating tobe freed from the surface of the balloon and deposited at theintervention site. The amount of coating transferred upon deployment canbe determined using, e.g., test methods as described herein.

Drug-Delivery Balloon (2)—Treatment of Restenosis with Cilostazol

A balloon is used to prevent and/or treat restenosis in an artery. Aballoon is coated as described herein with 50:50 PLGA-Ester End Group(MW˜19 kD, degradation rate ˜1-2 months) and cilostazol. The coatedballoon is positioned at the arterial intervention site. The balloon isinflated to at least 25% below its nominal inflation pressure. Theballoon is deflated and removed from the intervention site, allowing thecoating to be freed from the surface of the balloon and deposited at theintervention site where it can act to prevent further platelet binding.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (3)—Promotion of Healing Using CD34 Antibodies

A coated balloon is used to promote healing in a damaged artery. Aballoon is coated as described herein with 50:50 PLGA-Ester End Group(MW˜19 kD, degradation rate ˜1-2 months) and CD34 antibodies. The coatedballoon is positioned at the arterial intervention site. The balloon isinflated to at least 25% below its nominal inflation pressure. Theballoon is deflated and removed from the intervention site, allowing thecoating to be freed from the surface of the balloon and deposited at theintervention site where it can act to attract progenitor cells to thevessel wall. This can result in an acceleration of endothlialization.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (4)—Promotion of Healing Using an Agent thatProtects Endothelium or Improves EPC Function

A coated balloon is used to promote healing in a damaged artery. Aballoon is coated as described herein with 50:50 PLGA-Ester End Group(MW˜19 kD, degradation rate ˜1-2 months) and a statin (e.g.,cerivastatin), an ACE inhibitor, an angiotensin II type I receptorblocker, a PPAR-gamma agonist, a glitazone, or erythropoietin. Thecoated balloon is positioned at the arterial intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site where it can act to protect theendothelium and/or improve EPC colonization, maturation, or function.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (5)—Treatment of Atherosclerosis Using Adiponectin

A coated balloon is used to prevent and/or treat atherosclerosis in anartery. A balloon is coated as described herein with 50:50 PLGA-EsterEnd Group (MW˜19 kD, degradation rate ˜1-2 months) and adiponectin. Thecoated balloon is positioned at the arterial intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site where it can prevent inflammatorycell binding and promote generation of nitric oxide. The amount ofcoating transferred upon deployment can be determined using, e.g., testmethods as described herein.

Drug-Delivery Balloon (6)—Treatment of Atherosclerosis Using Batimastat

A coated balloon is used to prevent and/or treat atherosclerosis in anartery. A balloon is coated as described herein with 50:50 PLGA-EsterEnd Group (MW˜19 kD, degradation rate ˜1-2 months) and batimastat. Thecoated balloon is positioned at the arterial intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site where it can prevent vulnerableplaque rupture. The amount of coating transferred upon deployment can bedetermined using, e.g., test methods as described herein.

Drug-Delivery Balloon (7) Treatment of Reperfusion Injury

A coated balloon is used to prevent and/or treat reperfusion injury inan artery. A balloon is coated as described herein with 50:50 PLGA-EsterEnd Group (MW˜19 kD, degradation rate ˜1-2 months) and glucagon-likepeptide-1, erythropoietin, atorvastatin, or atrial natriuretic peptide.The coated balloon is positioned at the arterial intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site. The amount of coatingtransferred upon deployment can be determined using, e.g., test methodsas described herein.

Drug-Delivery Balloon (8)—Promotion of Angiogenesis

A coated balloon is used to promote angiogenesis. A balloon is coated asdescribed herein with 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months) and a fibroblast growth factor gene therapy agent(e.g., Generx, Cardium Therapeutics), or angiopoietin-1. The coatedballoon is positioned in a vessel in a tissue bed in need of betterperfusion. The balloon is inflated to at least 25% below its nominalinflation pressure. The balloon is deflated and removed from theintervention site, allowing the coating to be freed from the surface ofthe balloon and deposited at the intervention site where it can promoteangiogenesis. The amount of coating transferred upon deployment can bedetermined using, e.g., test methods as described herein.

Coated Cutting Balloon (9)—Treatment of Thrombosis Using Dipyridamole

A cutting balloon is used to prevent and/or treat thrombosis in anartery. A cutting balloon is coated with 50:50 PLGA-Ester End Group(MW˜19 kD, degradation rate ˜1-2 months) and dipyridamole. The coatedcutting balloon is positioned at the arterial intervention site. Theballoon is inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site to cause local release of t-PA tobreak up clots and/or prevent clot formation. The amount of coatingtransferred upon deployment can be determined using, e.g., test methodsas described herein.

Example 16 Drug-Delivery Balloon Catheter for Treatment of the Trachea

Drug-Delivery Balloon (1)—Prevention of Discomfort from the Use of anEndotracheal Tube Using Betamethasone or Lidocaine

A coated balloon catheter is used to prevent discomfort resulting fromthe use of an endotracheal tube. Prior to insertion of the endotrachealtube, procedure, a compliant balloon is coated with 50:50 PLGA-Ester EndGroup (MW˜19 kD, degradation rate ˜1-2 months) and betamethasone (0.05%)or lidocaine (2.0-4.0%), positioned in the endotracheal interventionsite and inflated to at least 25% below its nominal inflation pressure.The balloon is deflated and removed from the intervention site, allowingthe coating to be freed from the surface of the balloon and deposited atthe intervention site. The amount of coating transferred upon deploymentcan be determined using, e.g., test methods as described herein.

Drug-Delivery Balloon (2)—Reduction of Discomfort from the Use of anEndotracheal Tube Using Betamethasone or Lidocaine

A coated balloon catheter is used to reduce discomfort resulting fromthe use of an endotracheal tube. After the endotracheal procedure, acompliant balloon is coated with 50:50 PLGA-Ester End Group (MW˜19 kD,degradation rate ˜1-2 months) and betamethasone (0.05%) or lidocaine(2.0-4.0%), positioned in the endotracheal intervention site andinflated to at least 25% below its nominal inflation pressure. Theballoon is deflated and removed from the intervention site, allowing thecoating to be freed from the surface of the balloon and deposited at theintervention site. The amount of coating transferred upon deployment canbe determined using, e.g., test methods as described herein.

Drug-Delivery Balloon (3)—Improved Healing and Reduction of ScarringFollowing Laryngeal/Tracheal Surgery

A coated balloon catheter is used to improve healing and reduce scarringfollowing laryngeal/tracheal surgery. After the endotracheal procedure,a compliant balloon is coated with 50:50 PLGA-Ester End Group (MW˜19 kD,degradation rate ˜1-2 months) and mitomycin C (0.4-0.5 mg/ml or˜0.04-0.05%) or heparin (5000 U/ml) positioned in the endotrachealintervention site and inflated to at least 25% below its nominalinflation pressure. The balloon is deflated and removed from theintervention site, allowing the coating to be freed from the surface ofthe balloon and deposited at the intervention site. The amount ofcoating transferred upon deployment can be determined using, e.g., testmethods as described herein. The procedure is repeated as necessary toensure adequate delivery of active agent over the course of the woundhealing process.

Example 17 Drug-Delivery Balloon Catheter for Treatment of the Esophagus

Drug-Delivery Balloon (1)—Prevention of Discomfort Resulting from anEndoscopic Procedure Using Betamethasone or Lidocaine

A coated balloon catheter is used to prevent discomfort resulting froman endoscopic procedure. Prior to the endoscopic procedure, a compliantballoon is coated with 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months) and betamethasone (0.05%) or lidocaine (2.0-4.0%),positioned in the endoscopic intervention site and inflated to at least25% below its nominal inflation pressure. The balloon is deflated andremoved from the intervention site, allowing the coating to be freedfrom the surface of the balloon and deposited at the intervention site.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (2)—Reduction of Discomfort Resulting from anEndoscopic Procedure Using Betamethasone or Lidocaine

A coated balloon catheter is used to reduce discomfort resulting from anendoscopic procedure. After the endoscopic procedure, a compliantballoon is coated with 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months) and betamethasone (0.05%) or lidocaine (2.0-4.0%),positioned in the endoscopic intervention site and inflated to at least25% below its nominal inflation pressure. The balloon is deflated andremoved from the intervention site, allowing the coating to be freedfrom the surface of the balloon and deposited at the intervention site.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (3)—Reduction of Inflammation and Promotion ofHealing Following Endoscopic Surgery

A coated balloon catheter is used to reduce inflammation and promotehealing following endoscopic surgery. After the endoscopic surgery, acompliant balloon is coated with 50:50 PLGA-Ester End Group (MW˜19 kD,degradation rate ˜1-2 months) and mitomycin C and/or BacillusCalmette-Guerin is positioned in the endoscopic intervention site andinflated to at least 25% below its nominal inflation pressure. Theballoon is deflated and removed from the intervention site, allowing thecoating to be freed from the surface of the balloon and deposited at theintervention site. The amount of coating transferred upon deployment canbe determined using, e.g., test methods as described herein.

Example 18 Drug-Delivery Balloon Catheter for Treatment of a Cancer

Drug-Delivery Balloon (1)—Treatment of a Bladder Transitional CellCarcinoma

A coated balloon is used to treat a bladder transitional cell carcinoma.The balloon, which is large enough to contact the bladder walls wheninflated, is coated with a polymer combined with active agent sufficientto deliver the equivalent of either: 1) for administration immediatelyfollowing surgical resection, a combination intravesical treatment of1000 mg gemcitabine, or 75 mg docetaxel, or 30 mg thiotepa, followed(sequentially) by 40 mg mitomycin C, then the same combination treatmentevery week for 6 weeks, and followed by a maintenance regimen providingthe same combination treatment once a month for 12 months; or 2) foradministration starting 2 weeks after surgery, 50 million unitsInterferon Alpha 2b and 81 mg BCG once a week for 6 weeks, withmaintenance of up to 3 weekly instillations at 3 or 6 months, and thenonce every 6 to 12 months; or 3) for administration as a singleinstillation at the time of tumor resection, 50 mg doxorubicin, then thesame dose weekly for 4-8 weeks, then once a month to provide maintenanceas desired; or 4) for administration to treat existing disease, 30 mgthiotepa, then the same dose weekly for 4 to 8 weeks, depending onvolume of residual disease, then once a month to provide maintenance asdesired. In embodiments, the treatment is delivered in more than oneprocedure, e.g., a second balloon is used to deliver the maintenanceregimen. In treatment 2) the dose of BCG is reduced to ⅓, 1/10, 1/100 asneeded to prevent increased side effects. Treatments 1) through 4) aremade to include or not include hyaluronidase (rHuPH20, total dose 50-100U).

The balloon is inflated to at least 25% below its nominal inflationpressure and left in place for a period of time sufficient for transferof the coating to the bladder walls to take place, e.g., at least about2 to 30 minutes. The balloon is deflated and removed from theintervention site, allowing the coating to be freed from the surface ofthe balloon and deposited at the intervention site. The amount ofcoating transferred upon deployment can be determined using, e.g., testmethods as described herein. For example, the residual coating on theballoon or the coating within the bladder can be quantitated. Theprocedure can be repeated as deemed necessary.

In embodiments of the devices and methods of the invention, the amountof an active agent to be delivered is equal to at least about 35% ofthat used to coat the balloon. In these embodiments, with regard tointravesical therapy, to deliver a standard dosage of a drug, e.g., 50mg doxorubicin, the coating could comprise 50 mg×(35%)−1, or about 143mg doxorubicin. In related embodiments, layers comprising about 143 mgdoxorubicin are alternated with layers of a polymer, such that eachdoxorubicin layer delivers the appropriate weekly dose of doxorubicin asdictated by the treatment protocol. Combination treatments areadministered, e.g., by including in the coating layers of additionalactive agents in the appropriate treatment sequence.

Drug-Delivery Balloon (2)—Treatment of a Urinary Tract Transitional CellCarcinoma

A coated balloon is used to treat a urinary tract transitional cellcarcinoma. A balloon is coated with alternating layers of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) andsufficient active agent to deliver either about 10-40 mg mitomycin Cwith or without hyaluronic acid (rHuPH20, total dose 50-100 U), and/or10-81 mg bacillus Calmette-Guerin. The coated balloon is loaded into aFoley-type catheter and the balloon is positioned at a urethral lesionsite. The balloon is inflated to at least 25% below its nominalinflation pressure. The balloon is deflated and removed from theintervention site, allowing the coating to be freed from the surface ofthe balloon and deposited at the intervention site. The amount ofcoating transferred upon deployment can be determined using, e.g., testmethods as described herein.

Example 19 Drug-Delivery Balloon Catheter for Treatment of NeurovascularIndications

Drug-Delivery Balloon (1)—Treatment of Post-Stroke Thrombolysis

A coated balloon is used to treat post-stroke thrombolysis. Localdelivery of a sustained treatment can circumvent the risk associatedwith infusion of agents in the local vicinity of a vascular occlusion,which can result in severe bleeding. A balloon is coated withalternating layers of 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months) and a thrombolytic drug, e.g., tissue plasminogenactivator (tPA), melagatran, lanoteplase, reteplase, staphylokinase,streptokinase, tenecteplase, urokinase, or any combination thereof. Thecoated balloon is positioned within the vessel near the site ofthrombolysis as desired and inflated to at least 25% below its nominalinflation pressure. The balloon is deflated and removed from theintervention site, allowing the coating to be freed from the surface ofthe balloon and deposited at the intervention site. The amount ofcoating transferred upon deployment can be determined using, e.g., testmethods as described herein.

Drug-Delivery Balloon (2)—Treatment with a Neuroprotective Agent AfterStroke

A coated balloon is used to administer a neuroprotective agent afterstroke. A balloon is coated with alternating layers of 50:50 PLGA-EsterEnd Group (MW˜19 kD, degradation rate ˜1-2 months) and a neuroprotectivedrug, e.g., resveratrol, a PARP-1 inhibitor (includingimidazoquinolinone, imidazpyridine, and isoquinolindione). Resveratrolis an antioxidant that has been shown to preserve mitochondrial functionand improve neurological deficits after cerebral ischemia that couldprove more effective when delivered locally in a controlled fashion thanwhen delivered intravenously. The coated balloon is positioned withinthe vessel near the ischemic site as desired and inflated to at least25% below its nominal inflation pressure. The balloon is deflated andremoved from the intervention site, allowing the coating to be freedfrom the surface of the balloon and deposited at the intervention site.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (3)—Treatment of Malignant Glioma

A coated balloon is used to treat a glioma. Solid paclitaxel, is mixedwith poly[bis(p-carboxyphenoxy) propane-sebacic acid] copolymer(PCPP-SA) (20:80), synthesized, e.g., according to the method of Domb,A. J., and R. Langer (J. Polym. Sci. 25:3373-3386 (1987)), the teachingsof which are incorporated herein by reference, to give a mixturecontaining 0, 20, 30, or 40% paclitaxel by weight. Thepaclitaxel-polymer mixture is dissolved in methylene chloride (Fluka,Switzerland) to give a 10% solution (w:v). The solvent is evaporatedwith a nitrogen stream to yield a dry powder. A compliant orsemi-compliant balloon is coated with the powder. The coated balloon isinserted into the glioma using methods known in the art for insertingimplants, e.g., it is inserted following surgery and resection beforethe incision is closed. The balloon is inflated in the space previouslyoccupied by the tumor, to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited within the tumor cavity. The amount of coating transferredupon deployment can be determined using, e.g., test methods as describedherein.

Alternatively, a coated balloon can be inflated within a tumor withoutfirst performing surgery. In this case, a non-compliant orsemi-compliant could be used.

Local delivery of chemotherapeutic agents, and polymer selection, aredescribed, e.g., in U.S. Pat. No. 5,626,862, “Controlled local deliveryof chemotherapeutic agents for treating solid tumors,” incorporatedherein by reference in its entirety.

The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (4)—Treatment with a Stabilizing or Healing AgentAfter Cerebral Aneurysm

A coated balloon is used to administer a stabilizing or healing agentafter cerebral aneurysm, e.g., to prevent the vessel from rupturing. Aballoon is coated with alternating layers of 50:50 PLGA-Ester End Group(MW˜19 kD, degradation rate ˜1-2 months) and a stabilizing or healingagent, e.g., a polymer matrix (to prevent rupture), doxycyclin (toaccelerate the healing response), or a combination thereof. The coatedballoon is positioned at the intervention site and inflated to at least25% below its nominal inflation pressure The balloon is deflated andremoved from the intervention site, allowing the coating to be freedfrom the surface of the balloon and deposited at the intervention site.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Related information is available in the literature, e.g., in Mocco, etal., March 2009, “Pharos neurovascular intracranial stent: Elective usefor a symptomatic stenosis refractory to medical therapy,” CatheterCardiovasc Interv (Epub); Wang, et al., 2008, “Treatment with melagatranalone or in combination with thrombolytic therapy reduced ischemic braininjury,” Exp Neurol 213(1):171-175; Yepes, et al., 2009, “Tissue-typeplasminogen activator in the ischemic brain: more than a thrombolytic,”Trends Neurosci 32(1):48-55; Yousuf, et al., 2009, “Resveratrol exertsits neuroprotective effect by modulating mitochondrial dysfunction andassociated cell death during cerebral ischemia,” Brain Res.1250:242-253; Moroni, et a., 2009, “Post-ischemic brain damage:targetingPARP-1 within the ischemic neurovascular units as a realistic avenue tostroke treatment,” FEBS J 276(1):36-45; Eltze, et al., 2008,“Imidazoquinolinone, imidazopyridine, and isoquinolindione derivativesas novel and potent inhibitors of the poly(ADP-ribose) polymerase(PARP): a comparison with standard PARP inhibitors,” Mol Pharmacol.74(6):1587-1598; Raganath, et al., Jun. 20, 2009, “Hydrogel matrixentrapping PLGA-paclitaxel microspheres: drug delivery with nearzero-order release and implantability advantages for malignant braintumour,” Pharm Res (Epub); Kelly, et al., 2008, “Double-balloon trappingtechnique for embolization of a large wide-necked superior cerebellarartery aneurysm: case report,” Neurosurgery 63(4 Suppl 2):291-292.

Example 20 Drug-Delivery Device for Urologic and Reproductive Care

Drug-Delivery Balloon (1)—Treatment of a Urinary Tract Infection

A coated balloon is used to prevent and/or treat a urinary tractinfection. Sustained local release of an antibiotic agent eliminates theneed for systemic treatment that can raise concerns about thedevelopment of antibiotic resistance. Furthermore, systemicadministration of antibiotic agents is associated with adverse sideeffects including gastrointestinal upset, and oral and vaginalcandidiasis. A drug-releasing matrix adhered to the urethral wall couldprovide high local concentrations of drugs without producing negativeside effects. In a representative example, a balloon is coated withalternating layers of 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months) and an antibiotic, e.g., erythromycin, TMP-SMX,cephalexin, ciprofloxacin, or nitrofurantoin. The coated balloon ispositioned within the urethra and inflated to at least 25% below itsnominal inflation pressure. Upon deflation and removal of the balloonfrom the intervention site, at least about 20% to at least about 40% ofthe coating is freed from the surface of the balloon and is deposited atthe intervention site. The amount of coating transferred upon deploymentcan be determined using, e.g., test methods as described herein. Inparticular examples, the agent is delivered for at least 3-6 months.

For a patient having an indwelling J ureteral stent (e.g.,triclosan-eluting ureteral stents), a triclosan-eluting polymer matrixcan be transferred to the stented area, e.g., to supplementadministration of the triclosan from the stent.

Treatment and prevention of urinary tract infections has been describedin the literature, e.g., by Albert, et al., 2004, “Antibiotics forpreventing recurrent urinary tract infection in non-pregnant women,”Cochrane Database Syst. Rev. 3, CD001209; Borchert, et al., 2008,“Prevention and treatment of urinary tract infection with probiotics:Review and research perspective,” Indian J. Urol. 24(2):139-144; Salo,et al., 2009, “Biofilm formation by Escherichia coli isolated frompatients with urinary tract infections,” Clin Nephrol. 71(5): 501-507;Kehinde, et al., 2004, “Bacteriology of urinary tract infectionassociated with indwelling J ureteral stents,” J. Endourol.18(9):891-896; Cadieux, et al., Jun. 19, 2009, “Use of triclosan-elutingureteral stents in patients with long-term stents,” J. Endourol. (Epub).

Drug-Delivery Balloon (2)—Treatment of a Tubo-Ovarian Abcess

A coated balloon is used to treat a tubo-ovarian abcess. A balloon iscoated as described herein with alternating layers of 50:50 PLGA-EsterEnd Group (MW˜19 kD, degradation rate ˜1-2 months) and an antibioticagent, e.g., clindamycin in combination with gentamycin. The coatedballoon is positioned at the intervention site, e.g., within thefallopian tube, and inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site. The amount of coatingtransferred upon deployment can be determined using, e.g., test methodsas described herein. The procedure is repeated as necessary, e.g., toextend treatment or to administer a different antibiotic. In an example,the coating is designed to release the agents over a period of at leastabout two weeks.

Drug-Delivery Balloon (3)—Treatment of Benign Prostatic Hyperplasia

A coated balloon is used to treat benign prostatic hyperplasia (BPH). Aballoon is coated as described herein with alternating layers of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months) and anantibiotic agent combined with an antiinflammatory therapy, e.g.,ciprofloxacin and alfuzosin. The coated balloon is inserted into theprostate tissue through the rectum using a needle and ultrasoundguidance and inflated to at least 25% below its nominal inflationpressure. The balloon is deflated and removed from the interventionsite, allowing the coating to be freed from the surface of the balloonand deposited at the intervention site. The amount of coatingtransferred upon deployment can be determined using, e.g., test methodsas described herein. Methods for inserting implants into the prostateare known in the art and have been described in, e.g., U.S. Pat. No.7,442,162, “Method and apparatus for treatment planning using implantedradioactive seeds,” U.S. Pat. No. 7,282,020, “Deflectable implantationdevice and method of use,” incorporated herein by reference in theirentirety. Methods for visualizing a treatment area and planninginstrument insertion are described, e.g., in U.S. Pat. No. 7,171,255,“Virtual reality 3D visualization for surgical procedures” and U.S. Pat.No. 6,610,013, “3D ultrasound-guided intraoperative prostatebrachytherapy,” incorporated herein by reference in their entirety.

Drug-Delivery Balloon (4)—Hormone Delivery

A coated balloon is used to administer a hormone vaginally to alleviatethe symptoms of menopause. A balloon is coated as described herein withalternating layers of 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months), and either estrogen (17β-estradiol can beadministered at about 200 micrograms/day) for administration to apatient not having a uterus, or a combination of estrogen andprogesterone to a patient having an intact uterus. The coated balloon ispositioned at the vaginal intervention site and inflated to at least 25%below its nominal inflation pressure. The balloon is deflated andremoved from the intervention site, allowing the coating to be freedfrom the surface of the balloon and deposited at the intervention site.The amount of coating transferred upon deployment can be determinedusing, e.g., test methods as described herein.

Drug-Delivery Balloon (5)—Contraceptive

A coated balloon is used to administer a hormone contraceptive. Aballoon is coated as described herein with alternating layers of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months), andetonogestrel at a total dosage sufficient to provide a concentration ofabout 150 to 900 pg/ml for a period of about 3 years, accounting for theportion of coating predicted to transfer to the intervention site.

The coated balloon is positioned at the intervention site, e.g., at alocation near or within the reproductive organs, at an intramuscularlocation, or at a subcutaneous location, inflated to at least 25% belowits nominal inflation pressure, then deflated and removed. In women thedrug is administered, e.g., at anytime starting on Day 1 of menstrualbleeding and ending on Day 5 or as determined by a physician based onparameters including release rate. The amount of coating transferredupon deployment can be determined using, e.g., test methods as describedherein. Etonogestrel and its use as a contraceptive via administrationto either a male or female subject is described, e.g., in U.S. Pat. No.7,323,454, “Etonogestrel esters,” and in the labeling for Implanon™etonogestrel implant (Organon USA Inc.).

Drug-Delivery Balloon (6)—Fertility Drug

A coated balloon is used to administer a hormone contraceptive. Aballoon is coated as described herein with alternating layers of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months), andclomiphene citrate (Seraphene or Clomid) in an amount sufficient todeliver the equivalent of an oral dosage of 25 milligrams to 150milligrams once a day for five days.

The coated balloon is positioned at the intervention site, e.g., at alocation near or within the reproductive organs, at an intramuscularlocation, or at a subcutaneous location, inflated to at least 25% belowits nominal inflation pressure, then deflated and removed. The drug isadministered, e.g., early in a woman's menstrual cycle, e.g., days 2through 6 or as determined by a physician based on parameters includingrelease rate. The amount of coating transferred upon deployment can bedetermined using, e.g., test methods as described herein.

Response is monitored by methods known to those of skill in the art,e.g., blood estrogen measurement, ultrasound of the ovaries, andmeasurement of luteinizing hormone levels.

Example 21 Drug-Delivery Balloon Catheter for Treatment of Infection

Drug-Delivery Device—(1)—Orthopedic Implant

A coated balloon is used to treat or prevent staphylococcal infection ofan orthopedic implant, either alone or in conjunction with debridement.A balloon is coated as described herein with alternating layers of 50:50PLGA-Ester End Group (MW˜19 kD, degradation rate ˜1-2 months), animaging agent, and a combination of the antibiotics ciprofloxacin andrifampicin. The coated balloon is positioned at the intervention site,e.g., adjacent to the implant, with or without the aid of imagingguidance, inflated to at least 25% below its nominal inflation pressure,then deflated and removed. The amount of coating transferred upondeployment can be determined using, e.g., test methods as describedherein.

The procedure is repeated as necessary, e.g., to administer multipletreatments around the implant. In an example, the coating is designed torelease the agents over a period of at least about two weeks. Forprophylaxis, the coating is designed to release the agents over a longerperiod of time, e.g., at least about 1 year and/or longer. When usingthe devices and methods of the invention, antibiotic and other agentsare generally administered to achieve local concentrations comparable tothose achieved locally when systemic dosages, including IV, SC, ortypical oral dosages (e.g., rifampicin, 1 coated 450-mg tablet every 12hours, and ciprofloxacin, 750 mg every 12 hours by mouth) are given. Thelocally-administered dosages are much lower overall than the oraldosages, and better tolerated by patients.

Drug-Delivery Balloon (2)—Infection at a Cannulized or Cannulizable Site

A coated balloon is used to treat or prevent infection at a cannulizedor cannulizable site. A balloon is coated as described herein withalternating layers of 50:50 PLGA-Ester End Group (MW˜19 kD, degradationrate ˜1-2 months), an imaging agent, and an antibiotic, e.g., vancomycinor ciprofloxacin. The coated balloon is deployed through the catheterand positioned within the catheter, with or without the aid of imagingguidance, inflated to at least 25% below its nominal inflation pressure,then deflated and removed. The amount of coating transferred upondeployment can be determined using, e.g., test methods as describedherein.

In an example, the coating is designed to release the agents over aperiod of at least about one week, and/or for as long as the site is toremain cannulized. In cases where cannulization time is indefinite, theprocess can be repeated as necessary for prevention of new infections,or as new infections occur.

In a related example, the devices and methods of the invention are usedto percutaneously administer antibiotics at an intervention site withintissue in the vicinity of the infection.

Treatment and prevention of hemodialysis cather infections is described,e.g., by Saxena, et al., 2005, “Haemodialysis catheter-relatedbloodstream infections: current treatment options and strategies forprevention,” Swiss Med Wkly 135:127-138.

Example 22 Crystallinity of Drug on a Device

The presence and or quantification of the Active agent crystallinity canbe determined from a number of characterization methods known in theart, but not limited to, XRPD, vibrational spectroscopy (FTIR, NIR,Raman), polarized optical microscopy, calorimetry, thermal analysis andsolid-state NMR.

X-Ray Diffraction to Determine the Presence and/or Quantification ofActive Agent Crystallinity

Active agent and polymer coated proxy substrates are prepared using 316Lstainless steel coupons for X-ray powder diffraction (XRPD) measurementsto determine the presence of crystallinity of the active agent. Thecoating on the coupons is equivalent to the coating on the stentsdescribed herein. Coupons of other materials described herein, such ascobalt-chromium alloys, may be similarly prepared and tested. Likewise,substrates such as stents, or other medical devices described herein maybe prepared and tested. Where a coated stent is tested, the stent may becut lengthwise and opened to lay flat in a sample holder.

For example XRPD analyses are performed using an X-ray powderdiffractometer (for example, a Bruker D8 Advance X-ray diffractometer)using Cu Kα radiation. Diffractograms are typically collected between 2and 40 degrees 2 theta. Where required low background XRPD sampleholders are employed to minimize background noise.

The diffractograms of the deposited active agent are compared withdiffractograms of known crystallized active agents, for examplemicronized crystalline sirolimus in powder form. XRPD patterns ofcrystalline forms show strong diffraction peaks whereas amorphous showdiffuse and non-distinct patterns. Crystallinity is shown in arbitraryIntensity units.

A related analytical technique which may also be used to providecrystallinity detection is wide angle scattering of radiation (e.g.;Wide Anle X-ray Scattering or WAXS), for example, as described in F.Unger, et al., “Poly(ethylene carbonate): A thermoelastic andbiodegradable biomaterial for drug eluting stent coatings?” Journal ofControlled Release, Volume 117, Issue 3, 312-321 (2007) for which thetechnique and variations of the technique specific to a particularsample would be obvious to one of skill in the art.

Raman Spectroscopy

Raman spectroscopy, a vibrational spectroscopy technique, can be useful,for example, in chemical identification, characterization of molecularstructures, effects of bonding, identification of solid state form,environment and stress on a sample. Raman spectra can be collected froma very small volume (<1 μm3); these spectra allow the identification ofspecies present in that volume. Spatially resolved chemical information,by mapping or imaging, terms often used interchangeably, can be achievedby Raman microscopy.

Raman spectroscopy and other analytical techniques such as described inBalss, et al., “Quantitative spatial distribution of sirolimus andpolymers in drug-eluting stents using confocal Raman microscopy” J. ofBiomedical Materials Research Part A, 258-270 (2007), incorporated inits entirety herein by reference, and/or described in Belu et al.,“Three-Dimensional Compositional Analysis of Drug Eluting Stent CoatingsUsing Cluster Secondary Ion Mass Spectroscopy” Anal. Chem. 80: 624-632(2008) incorporated herein in its entirety by reference may be used.

For example, to test a sample using Raman microscopy and in particularconfocal Raman microscopy, it is understood that to get appropriateRaman high resolution spectra sufficient acquisition time, laser power,laser wavelength, sample step size and microscope objective need to beoptimized. For example a sample (a coated stent) is prepared asdescribed herein. Alternatively, a coated coupon could be tested in thismethod. Maps are taken on the coating using Raman microscopy. A WITecCRM 200 scanning confocal Raman microscope using a Nd:YAG laser at 532nm is applied in the Raman imaging mode. The laser light is focused uponthe sample using a 10× dry objective (numerical aperture 0.90), and thefinely focused laser spot is scanned into the sample. As the laser scansthe sample, over each 0.33 micron interval a Raman spectrum with highsignal to noise is collected using 0.3 seconds of integration time. Eachconfocal cross-sectional image of the coatings displays a region 70 μmwide by 10 μm deep, and results from the gathering of 6300 spectra witha total imaging time of 32 min.

Multivariate analysis using reference spectra from samples of rapamycin(amorphous and crystalline) and polymer are used to deconvolve thespectral data sets, to provide chemical maps of the distribution.

Infrared (IR) Spectroscopy for In-Vitro Testing

Infrared (IR) Spectroscopy such as FTIR and ATR-IR are well utilizedtechniques that can be applied to show, for example, the quantitativedrug content, the distribution of the drug in the sample coating, thequantitative polymer content in the coating, and the distribution ofpolymer in the coating. Infrared (IR) Spectroscopy such as FTIR andATR-IR can similarly be used to show, for example, drug crystallinity.The following table (Table 2) lists the typical IR materials for variousapplications. These IR materials are used for IR windows, diluents orATR crystals.

TABLE 2 MATERIAL NACL KBR CSI AGCL GE ZNSE DIAMOND Transmission40,000~625 40,000~400 40,000~200 25,000~360 5,500~625 20,000~45440,000~2,500 & range (cm−1) 1667-33 Water sol 35.7 53.5 44.4 Insol.Insol. Insol. Insol. (g/100 g, 25 C.) Attacking Wet Wet Wet AmmoniumH2SO4, Acids, K2Cr2Os, materials Solvents Solvents Solvents Salts aquastrong conc. regin alkalies, H2SO4 chlorinated solvents

In one test, a coupon of crystalline ZnSe is coated by the processesdescribed herein, creating a PDPDP (Polymer, Drug, Polymer, Drug,Polymer) layered coating that is about 10 microns thick. The coatedcoupon is analyzed using FTIR. The resulting spectrum shows crystallinedrug as determined by comparison to the spectrum obtained for thecrystalline form of a drug standard (i.e. a reference spectrum).

Differential Scanning Calorimetry (DSC)

DSC can provide qualitative evidence of the crystallinity of the drug(e.g. rapamycin) using standard DSC techniques obvious to one of skilledin the art. Crystalline melt can be shown using this analytical method(e.g. rapamycin crystalline melting—at about 185 decrees C. to 200degrees C., and having a heat of fusion at or about 46.8 J/g). The heatof fusion decreases with the percent crystallinity. Thus, the degree ofcrystallinity could be determined relative to a pure sample, or versus acalibration curve created from a sample of amorphous drug spiked andtested by DSC with known amounts of crystalline drug. Presence (atleast) of crystalline drug on a stent could be measured by removing(scraping or stripping) some drug from the stent and testing the coatingusing the DSC equipment for determining the melting temperature and theheat of fusion of the sample as compared to a known standard and/orstandard curve.

Confocal Raman Microscopy

Confocal Raman Microscopy can provide nondestructive depth analysis andallows coating specific Raman spectral features to be obtained (Bugay etal., “Raman Analysis of Pharmaceuticals,” in “Applications ofVibrational Spectroscopy in Pharmaceutical Research and Development,”Ed. Pivonka, D. E., Chalmers, J. M., Griffiths, P. R. (2007) Wiley andSons). In confocal Raman microscopy an aperture is place in a focalplace of the collected beam. This limitation defines a shallow portionof the depth of field and thereby provides definition of the z-axisspatial resolution for data collection. By adjusting the aperture andmoving the focus within the sample, the sampling position within thesample moves. Moving the sample focus from the top surface, deeper intothe specimen facilitates nondestructive depth analysis.

Example 23 Detection of Coating Remaining on a Device Following Use

The ability to uniformly coat a device with controlled composition andthickness using electrostatic capture in a rapid expansion ofsupercritical solution (RESS) experimental series has been demonstrated.

The coating remaining on a device following use of the device may beexamined by any of the following test methods. For example, the coatingremaining on a device following use is an indication of the maximumamount of coating freed from the device. In an in-vivo or in-vitromethod, an embodiment of the device that is removed from the subjectonce used is tested for remaining coating (for example, a balloon).

Scanning Electron Microscopy (SEM)

Stents are observed by SEM using a Hitachi S-4800 with an acceleratingvoltage of 800V. Various magnifications are used to evaluate theintegrity, especially at high strain regions. SEM can provide top-downand cross-section images at various magnifications. Coating uniformityand thickness can also be assessed using this analytical technique.

Pre- and post-expansions stents are observed by SEM using a HitachiS-4800 with an accelerating voltage of 800V. Various magnifications areused to evaluate the integrity of the layers, especially at high strainregions.

Scanning Electron Microscopy (SEM) with Focused Ion Beam (FIB)

Stents as described herein, and or produced by methods described hereinare visualized using SEM-FIB analysis. Alternatively, a coated couponcould be tested in this method. Focused ion beam FIB is a tool thatallows precise site-specific sectioning, milling and depositing ofmaterials. FIB can be used in conjunction with SEM, at ambient or cryoconditions, to produce in-situ sectioning followed by high-resolutionimaging. Cross-sectional FIB images may be acquired, for example, at7000× and/or at 20000× magnification. An even coating of consistentthickness is visible.

Optical Microscopy

An Optical micrscope may be used to create and inspect the stents and toempirically survey the coating of the substrate (e.g. coatinguniformity). Nanoparticles of the drug and/or the polymer can be seen onthe surfaces of the substrate using this analytical method. Followingsintering, the coatings can be see using this method to view the coatingconformaliy and for evidence of crystallinity of the drug.

In-vitro test: One sample of the coated compliant balloon prepared inExample 1 is secured to a balloon catheter. A segment of optically clearTYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Available fromMcMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filled withphosphate-buffered saline solution and immersed in a water bath at 37°C. to mimic physiological conditions of deployment into a subject. Thecoated balloon is inserted into the tubing and the balloon is inflatedto at least 25% below the balloon's nominal pressure to mechanicallytransfer the coating from the balloon to the tubing wall. The balloon isdeflated and removed from the tubing. Scanning Electron Microscopy isperformed on the tubing and the balloon (which is inflated to at least25% below the balloon's nominal pressure, at least) to determine thepresence and amount of coating transferred to the tubing and/or theamount of coating freed, dissociated, and/or transferred from theballoon.

Example 24 Detection of Coating Freed from a Device Following Use

The ability to uniformly coat a device with controlled composition andthickness using electrostatic capture in a rapid expansion ofsupercritical solution (RESS) experimental series has been demonstrated.

The amount of coating freed from the device may be determined by testingfor the amount of coating deposited to the target site. In an in-vivo orin-vitro method, the target site is tested for coating that is freedfrom the device, extruded from the device, dissociated from the device,transferred from the device, or sheared from the device.

Scanning Electron Microscopy (SEM)

Stents are observed by SEM using a Hitachi S-4800 with an acceleratingvoltage of 800V. Various magnifications are used to evaluate theintegrity, especially at high strain regions. SEM can provide top-downand cross-section images at various magnifications. Coating uniformityand thickness can also be assessed using this analytical technique.

Pre- and post-expansions stents are observed by SEM using a HitachiS-4800 with an accelerating voltage of 800V. Various magnifications areused to evaluate the integrity of the layers, especially at high strainregions.

Scanning Electron Microscopy (SEM) with Focused Ion Beam (FIB)

Stents as described herein, and or produced by methods described hereinare visualized using SEM-FIB analysis. Alternatively, a coated couponcould be tested in this method. Focused ion beam FIB is a tool thatallows precise site-specific sectioning, milling and depositing ofmaterials. FIB can be used in conjunction with SEM, at ambient or cryoconditions, to produce in-situ sectioning followed by high-resolutionimaging. Cross-sectional FIB images may be acquired, for example, at7000× and/or at 20000× magnification. An even coating of consistentthickness is visible.

Optical Microscopy

An Optical micrscope may be used to create and inspect the stents and toempirically survey the coating of the substrate (e.g. coatinguniformity). Nanoparticles of the drug and/or the polymer can be seen onthe surfaces of the substrate using this analytical method. Followingsintering, the coatings can be see using this method to view the coatingconformaliy and for evidence of crystallinity of the drug.

Scintigraphy

Use of a radiolabeled drug and/or polymer and/or coating generally canbe employed to monitor amount of material freed, dissociated, and/ortransferred from the substrate, and/or the amount of materialtransferred to, delivered to and/or deposited at the intervention site.It may also and/or alternatively be used to determine degradation rateof the polymer and/or release rate of the drug from the deliveredcoating.

In-Vivo Test: One sample of the coated compliant balloon prepared inExample 1 is prepared using a coating comprising a radiolabelled drug.The balloon is secured to a balloon catheter. A segment of opticallyclear TYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″ (Availablefrom McMaster-Carr Part Number: 5114K11 (www.mcmaster.com)) is filledwith phosphate-buffered saline solution and immersed in a water bath at37° C. to mimic physiological conditions of deployment into a subject.The coated balloon is inserted into the tubing and the balloon isinflated to at least 25% below the balloon's nominal pressure tomechanically transfer the coating from the balloon to the tubing wall.The balloon is deflated and removed from the tubing. The deflatedballoon is placed into a vial containing scintillation cocktail,inflated to the deployment presure and the amount of radiation emittedis determined in a liquid scintillation counter. The section of tubingexposed to the balloon is cut away and splayed open to expose theinterior. The section of tubing is placed into a vial containingscintillation cocktail, and the amount of radiation emitted isdetermined in a liquid scintillation counter.

Imaging Techniques

Use of an imaging agent and/or polymer and/or coating generally can beemployed to monitor amount of material freed, dissociated, and/ortransferred from the substrate, and/or the amount of materialtransferred to, delivered to and/or deposited at the intervention site.It may also and/or alternatively be used to determine degradation rateof the polymer and/or release rate of the drug from the deliveredcoating.

In-Vivo Test: One sample of the coated compliant balloon prepared inExample 1 is prepared using a coating comprising a imaging agent such asbarium sulfate. The balloon is secured to a balloon catheter. A segmentof optically clear TYGON® B-44-3 tubing with O.D.=0.125″, I.D.=0.0625″(Available from McMaster-Carr Part Number: 5114K11 (www.mcmaster.com))is filled with phosphate-buffered saline solution and immersed in awater bath at 37° C. to mimic physiological conditions of deploymentinto a subject. The coated balloon is inserted into the tubing and theballoon is inflated to at least 25% below the balloon's nominal pressureto mechanically transfer the coating from the balloon to the tubingwall. The balloon is deflated and removed from the tubing. The sectionof tubing exposed to the balloon is cut away and splayed open to exposethe interior. The section of tubing is placed into a x-ray fluoroscope,and the amount of coating deposited is determined.

Example 25 Determination and Detection of Coating Confromality

The ability to uniformly coat devices, e.g., pre- and post-expansionstents, and balloons, with controlled composition and thickness usingelectrostatic capture in a rapid expansion of supercritical solution(RESS) experimental series has been demonstrated.

Scanning Electron Microscopy (SEM)

Devices are observed by SEM using a Hitachi S-4800 with an acceleratingvoltage of 800V. Various magnifications are used to evaluate theintegrity, especially at high strain regions. SEM can provide top-downand cross-section images at various magnifications. Coating uniformityand thickness can also be assessed using this analytical technique.

Pre- and post-inflation balloons, for example, may be observed by SEMusing a Hitachi S-4800 with an accelerating voltage of 800V. Variousmagnifications may be used to evaluate the integrity of the layers, andor of the coating.

Scanning Electron Microscopy (SEM) with Focused Ion Beam (FIB)

Devices as described herein, and or produced by methods described hereinare visualized using SEM-FIB analysis. Alternatively, a coated couponcould be tested in this method. Focused ion beam FIB is a tool thatallows precise site-specific sectioning, milling and depositing ofmaterials. FIB can be used in conjunction with SEM, at ambient or cryoconditions, to produce in-situ sectioning followed by high-resolutionimaging. Cross-sectional FIB images may be acquired, for example, at7000× and/or at 20000× magnification. An even coating of consistentthickness is visible.

Optical Microscopy

An optical microscope may be used to create and inspect the devices andto empirically survey the coating of the substrate (e.g. coatinguniformity). Nanoparticles of the drug and/or the polymer can be seen onthe surfaces of the substrate using this analytical method. Followingsintering, the coatings can be see using this method to view the coatingconformality and for evidence of crystallinity of the drug.

Example 26 Visualization of Polymer/Active Agent Layers Coating a DeviceRaman Spectroscopy

As discussed herein, Raman spectroscopy can be applied to characterizethe chemical structure and relative concentrations of drug and polymercoatings. For example, confocal Raman Spectroscopy/microscopy can beused to characterize the relative drug to polymer ratio at the outer ˜1μm of the coated surface. In addition confocal Raman x-z or z (maps orline scans) microscopy can be applied to characterize the relative drugto polymer ratio as a function of depth. Additionally cross-sectionedsamples can be analysed. Raman spectroscopy and other analyticaltechniques such as described in Balss, et al., “Quantitative spatialdistribution of sirolimus and polymers in drug-eluting stents usingconfocal Raman microscopy” J. of Biomedical Materials Research Part A,258-270 (2007), incorporated in its entirety herein by reference, and/ordescribed in Belu et al, “Three-Dimensional Compositional Analysis ofDrug Eluting Stent Coatings Using Cluster Secondary Ion MassSpectroscopy” Anal. Chem. 80: 624-632 (2008) incorporated herein in itsentirety by reference may be used.

A sample (a coated substrate) is prepared as described herein. Imagesare taken on the coating using Raman Spectroscopy. Alternatively, acoated coupon could be tested in this method. To test a sample usingRaman microscopy and in particular confocal Raman microscopy, it isunderstood that to get appropriate Raman high resolution spectrasufficient acquisition time, laser power, laser wavelength, sample stepsize and microscope objective need to be optimized.

For example a WITec CRM 200 scanning confocal Raman microscope using aNd:YAG laser at 532 nm is applied in the Raman imaging mode to give x-zmaps. The sample is placed upon a piezoelectrically driven table, thelaser light is focused upon the sample using a 100× dry objective(numerical aperture 0.90), and the finely focused laser spot is scannedinto the sample. As the laser scans the sample, over each 0.33 microninterval a Raman spectrum with high signal to noise is collected using0.3 Seconds of integration time. Each confocal cross-sectional image ofthe coatings displays a region 70 μm wide by 10 μm deep, and resultsfrom the gathering of 6300 spectra with a total imaging time of 32 min.Multivariate analysis using reference spectra from samples of rapamycinand polymer are used to deconvolve the spectral data sets, to providechemical maps of the distribution.

In another test, spectral depth profiles (x-z maps) of samples areperformed with a CRM200 microscope system from WITec InstrumentsCorporation (Savoy, Ill.). The instrument is equipped with a Nd:YAGfrequency doubled laser (532 excitation), a single monochromator (Acton)employing a 600 groove/mm grating and a thermoelectrically cooled 1024by 128 pixel array CCD camera (Andor Technology). The microscope isequipped with appropriate collection optics that include a holographiclaser bandpass rejection filter (Kaiser Optical Systems Inc.) tominimize Rayleigh scatter into the monochromator. The Raman scatteredlight are collected with a 50 micron optical fiber. Using the “RamanSpectral Imaging” mode of the instrument, spectral images are obtainedby scanning the sample in the x, z direction with a piezo driven xyzscan stage and collecting a spectrum at every pixel. Typical integrationtimes are 0.3 s per pixel. The spectral images are 4800 total spectracorresponding to a physical scan dimension of 40 by 20 microns. Forpresentation of the confocal Raman data, images are generated based onunique properties of the spectra (i.e. integration of a Raman band, bandheight intensity, or band width). The microscope stage is modified witha custom-built sample holder that positioned and rotated the stentsaround their primary axis. The x direction is defined as the directionrunning parallel to the length of the stent and the z direction refersto the direction penetrating through the coating from the air-coating tothe coating-metal interface. Typical laser power is <10 mW on the samplestage. All experiments can be conducted with a plan achromat objective,100×NA=0.9 (Nikon).

Samples (n=5) comprising metal substrates made of L605 (0.05-0.15% C,1.00-2.00% Mn, maximum 0.040% Si, maximum 0.030% P, maximum 0.3% S,19.00-21.00% Cr, 9.00-11.00% Ni, 14.00-16.00% W, 3.00% Fe, and Bal. Co)and having coatings as described herein and/or produced by methodsdescribed herein can be analyzed. For each sample, three locations areselected along the substrate length. The three locations are locatedwithin one-third portions of the substrates so that the entire length ofthe substrate are represented in the data. The stent is then rotated 180degrees around the circumference and an additional three locations aresampled along the length. In each case, the data is collected from thestrut portion of the substrate. Six random spatial locations are alsoprofiled on coated coupon samples made of L605 and having coatings asdescribed herein and/or produced by methods described herein. The Ramanspectra of each individual component present in the coatings are alsocollected for comparison and reference. Using the instrument software,the average spectra from the spectral image data are calculated byselecting the spectral image pixels that are exclusive to each layer.The average spectra are then exported into GRAMS/AI v. 7.02 software(Thermo Galactic) and the appropriate Raman bands are fit to a Voigtfunction. The band areas and shift positions are recorded.

The pure component spectrum for each component of the coating (e.g.drug, polymer) are also collected at 532 and 785 nm excitation. The 785nm excitation spectra are collected with a confocal Raman microscope(WITec Instruments Corp. Savoy, Ill.) equipped with a 785 nm diodelaser, appropriate collection optics, and a back-illuminatedthermoelectriaclly cooled 1024×128 pixel array CCD camera optimized forvisible and infrared wavelengths (Andor Technology).

X-ray Photoelectron Spectroscopy (XPS)

XPS can be used to quantitatively determine elemental species andchemical bonding environments at the outer 5-10 nm of sample surface.The technique can be operated in spectroscopy or imaging mode. Whencombined with a sputtering source XPS can be utilized to give depthprofiling chemical characterization. XPS (ESCA) and other analyticaltechniques such as described in Belu et al., “Three-DimensionalCompositional Analysis of Drug Eluting Stent Coatings Using ClusterSecondary Ion Mass Spectroscopy” Anal. Chem. 80: 624-632 (2008)incorporated herein in its entirety by reference may be used.

For example, in one test, a sample comprising a stent coated by methodsdescribed herein and/or a device as described herein is obtained. XPSanalysis is performed on a sample using a Physical Electronics Quantum2000 Scanning ESCA. The monochromatic Al Kα source is operated at 15 kVwith a power of 4.5 W. The analysis is done at a 45° take off angle.Three measurements are taken along the length of each sample with theanalysis area ˜20 microns in diameter. Low energy electron and Ar⁺ ionfloods are used for charge compensation.

Time of Flight Secondary Ion Mass Spectrometery (TOF-SIMS)

TOF-SIMS can be used to determine molecular species (drug and polymer)at the outer 1-2 nm of sample surface when operated under staticconditions. The technique can be operated in spectroscopy or imagingmode at high spatial resolution. Additionally cross-sectioned samplescan be analysed. When operated under dynamic experimental conditions,known in the art, depth profiling chemical characterization can beachieved.

For example, to analyze the uppermost surface only, static conditions(for example a ToF-SIMS IV (IonToF, Munster)) using a 25 Kv Bi++ primaryion source maintained below 1012 ions per cm2 is used. Where necessary alow energy electron flood gun (0.6 nA DC) is used to charge compensateinsulating samples.

Cluster Secondary Ion Mass Spectrometry, may be employed for depthprofiling as described Belu et al., “Three-Dimensional CompositionalAnalysis of Drug Eluting Stent Coatings Using Cluster Secondary Ion MassSpectroscopy” Anal. Chem. 80: 624-632 (2008) incorporated herein in itsentirety by reference.

For example, a ballon coated as described herein is obtained. Theballoon is prepared for SIMS analysis by cutting it longitudinally andopening it up with tweezers. The balloon is then pressed into multiplelayers of indium foil with the outer diameter facing outward.

TOF-SIMS depth profiling experiments are performed using an Ion-TOF IVinstrument equipped with both Bi and SF5+ primary ion beam clustersources. Sputter depth profiling is performed in the dual-beam mode,whilst preserving the chemical integrity of the sample. The analysissource is a pulsed, 25-keV bismuth cluster ion source, which bombardedthe surface at an incident angle of 45° to the surface normal. Thetarget current is maintained at ˜0.3 pÅ (+10%) pulsed current with araster size of 200 um×200 um for all experiments. Both positive andnegative secondary ions are extracted from the sample into areflectron-type time-of-flight mass spectrometer. The secondary ions arethen detected by a microchannel plate detector with a post-accelerationenergy of 10 kV. A low-energy electron flood gun is utilized for chargeneutralization in the analysis mode.

The sputter source used is a 5-keV SF5+ cluster source also operated atan incident angle of 45° to the surface normal. For thin model sampleson Si, the SF5+ current is maintained at ˜2.7 nÅ with a 750 um×750 umraster. For the thick samples on coupons and for the samples on stents,the current is maintained at 6 nA with a 500 um×500 um raster. Allprimary beam currents are measured with a Faraday cup both prior to andafter depth profiling.

All depth profiles are acquired in the noninterlaced mode with a 5-mspause between sputtering and analysis. Each spectrum is averaged over a7.37 second time period. The analysis is immediately followed by 15seconds of SF5+ sputtering. For depth profiles of the surface andsubsurface regions only, the sputtering time was decreased to 1 secondfor the 5% active agent sample and 2 seconds for both the 25% and 50%active agent samples.

Temperature-controlled depth profiles are obtained using avariable-temperature stage with Eurotherm Controls temperaturecontroller and IPSG V3.08 software. samples are first placed into theanalysis chamber at room temperature. The samples are brought to thedesired temperature under ultra high-vacuum conditions and are allowedto stabilize for 1 minute prior to analysis. All depth profilingexperiments are performed at −100 C and 25 C.

Atomic Force Microscopy (AFM)

AFM is a high resolution surface characterization technique. AFM is usedin the art to provide topographical imaging, in addition when employedin Tapping Mode™ can image material and or chemical properties of thesurface. Additionally cross-sectioned samples can be analyzed. Thetechnique can be used under ambient, solution, humidified or temperaturecontrolled conditions. Other modes of operation are well known and canbe readily employed here by those skilled in the art.

A substrate having a coating as described herein is obtained. AFM isused to determine the structure of the drug polymer layers. AFM may beemployed as described in Ranade et al., “Physical characterization ofcontrolled release of paclitaxel from the TAXUS Express2 drug-elutingstent” J. Biomed. Mater. Res. 71(4):625-634 (2004) incorporated hereinin its entirety by reference.

Polymer and drug morphologies, coating composition, at least may bedetermined using atomic force microscopy (AFM) analysis. A multi-modeAFM (Digital Instruments/Veeco Metrology, Santa Barbara, Calif.)controlled with Nanoscope IIIa and NanoScope Extender electronics isused. Samples are examined in the dry state using AFM before elution ofthe drug (e.g. rapamycin). Samples are also examined at select timepoints through a elution period (e.g. 48 hours) by using an AFMprobe-tip and flow-through stage built to permit analysis of wetsamples. The wet samples are examined in the presence of the sameelution medium used for in-vitro kinetic drug release analysis (e.g.PBS-Tween20, or 10 mM Tris, 0.4 wt. % SDS, pH 7.4). Saturation of thesolution is prevented by frequent exchanges of the release medium withseveral volumes of fresh medium. TappingMode™ AFM imaging may be used toshow topography (a real-space projection of the coating surfacemicrostructure) and phase-angle changes of the AFM over the sample areato contrast differences in the materials properties. The AFM topographyimages can be three-dimensionally rendered to show the surface of acoated stent, which can show holes or voids of the coating which mayoccur as the polymer is absorbed and the drug is eluted over time, forexample.

Scanning Electron Microscopy (SEM) with Focused Ion Beam (FIB) Milling

Coatings on substrates as described herein, and or produced by methodsdescribed herein are visualized using SEM-FIB. Alternatively, a coatedcoupon could be tested in this method. Focused ion beam FIB is a toolthat allows precise site-specific sectioning, milling and depositing ofmaterials. FIB can be used in conjunction with SEM, at ambient or cryoconditions, to produce in-situ sectioning followed by high-resolutionimaging. FIB-SEM can produce a cross-sectional image of the polymer anddrug layers on the substrate. The image can be used to quantitate thethickness of the layers and uniformity of the layer thickness atmanufacture and at time points after stenting (or after in-vitro elutionat various time points).

A FEI Dual Beam Strata 235 FIB/SEM system is a combination of a finelyfocused Ga ion beam (FIB) accelerated by 30 kV with a field emissionelectron beam in a scanning electron microscope instrument and is usedfor imaging and sectioning the stents. Both beams focus at the samepoint of the sample with a probe diameter less than 10 nm. The FIB canalso produce thinned down sections for TEM analysis.

To prevent damaging the surface of the substrate with incident ions, aPt coating is first deposited via electron beam assisted deposition andion beam deposition prior to FIB sectioning. For FIB sectioning, the Gaion beam is accelerated to 30 kV and the sectioning process is about 2 hin duration. Completion of the FIB sectioning allows one to observe andquantify by SEM the thickness of the polymer layers that are, forexample, left on the substrate as they are absorbed.

Example 27 Determination of Secondary Structures Presence of aBiological Agent

Raman Spectroscopy

FT-Raman or confocal raman microscopy can be employed to determinesecondary structure of a biological Agent. For example fitting of theAmide I, II, or III regions of the Raman spectrum can elucidatesecondary structures (e.g. alpha-helices, beta-sheets). See, forexample, Iconomidou, et al., “Secondary Structure of Chorion Proteins ofthe Teleosetan Fish Dentex dentex by ATR FR-IR and FT-RamanSpectroscopy” J. of Structural Biology, 132, 112-122 (2000); Griebenow,et al., “On Protein Denaturation in Aqueous-Organic Mixtures but Not inPure Organic Solvents” J. Am Chem. Soc., Vol 118, No. 47, 11695-11700(1996).

Infrared (IR) Spectroscopy for In-Vitro Testing

Infrared spectroscopy, for example FTIR, ATR-IR and micro ATR-IR can beemployed to determine secondary structure of a biological Agent. Forexample fitting of the Amide I, II, of III regions of the infraredspectrum can elucidate secondary structures (e.g. alpha-helices,beta-sheets).

Example 28 Determination of the Microstructure of a Coating on a MedicalDevice

Atomic Force Microscopy (AFM)

AFM is a high resolution surface characterization technique. AFM is usedin the art to provide topographical imaging, in addition when employedin Tapping Mode™ can image material and or chemical properties of thesurface. Additionally cross-sectioned samples can be analyzed. Thetechnique can be used under ambient, solution, humidified or temperaturecontrolled conditions. Other modes of operation are well known and canbe readily employed here by those skilled in the art.

A device as described herein is obtained. AFM is used to determine themicrostructure of the coating. A stent as described herein is obtained.AFM may be employed as described in Ranade et al., “Physicalcharacterization of controlled release of paclitaxel from the TAXUSExpress2 drug-eluting stent” J. Biomed. Mater. Res. 71(4):625-634 (2004)incorporated herein in its entirety by reference.

For example, polymer and drug morphologies, coating composition, andphysical structure may be determined using atomic force microscopy (AFM)analysis. A multi-mode AFM (Digital Instruments/Veeco Metrology, SantaBarbara, Calif.) controlled with Nanoscope IIIa and NanoScope Extenderelectronics is used. Samples are examined in the dry state using AFMbefore elution of the drug (e.g. rapamycin). Samples are also examinedat select time points through a elution period (e.g. 48 hours) by usingan AFM probe-tip and flow-through stage built to permit analysis of wetsamples. The wet samples are examined in the presence of the sameelution medium used for in-vitro kinetic drug release analysis (e.g.PBS-Tween20, or 10 mM Tris, 0.4 wt. % SDS, pH 7.4). Saturation of thesolution is prevented by frequent exchanges of the release medium withseverl volumes of fresh medium. TappingMode™ AFM imaging may be used toshow topography (a real-space projection of the coating surfacemicrostructure) and phase-angle changes of the AFM over the sample areato contrast differences in the materials properties. The AFM topographyimages can be three-dimensionally rendered to show the surface of acoated stent, which can show holes or voids of the coating which mayoccur as the polymer is absorbed and the drug is released from thepolymer over time, for example.

Nano X-Ray Computer Tomography

Another technique that may be used to view the physical structure of adevice in 3-D is Nano X-Ray Computer Tomography (e.g. such as made bySkyScan), which could be used in an elution test and/or bioabsorbabilitytest, as described herein to show the physical structure of the coatingremaining on substrates at each time point, as compared to a scan priorto elution/bioabsorbtion.

Example 29 Determination of the Total Content of the Active Agent(and/or the Content of Active Agent Remaining on a Device Following anIntervention)

Determination of the total content of the active agent in a coatedsubstrate may be tested using techniques described herein as well asother techniques obvious to one of skill in the art, for example usingGPC and HPLC techniques to extract the drug from the coated substrateand determine the total content of drug in the sample.

UV-VIS can be used to quantitatively determine the mass of rapamycin (oranother active agent) coated onto the substrates. A UV-Vis spectrum ofRapamycin can be shown and a Rapamycin calibration curve can beobtained, (e.g. λ@277 nm in ethanol). Rapamycin is then dissolved fromthe coated substrate in ethanol, and the drug concentration and masscalculated.

In one test, the total amount of rapamycin (or another active agent)present in units of micrograms per substrate is determined by reversephase high performance liquid chromatography with UV detection(RP-HPLC-UV). The analysis is performed with modifications ofliterature-based HPLC methods for rapamycin (or the other active agent)that would be obvious to a person of skill in the art. The average drugcontent of samples (n=10) from devices comprising stents and coatings asdescribed herein, and/or methods described herein are tested.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. While embodiments of the presentinvention have been shown and described herein, it will be obvious tothose skilled in the art that such embodiments are provided by way ofexample only. Numerous variations, changes, and substitutions will nowoccur to those skilled in the art without departing from the invention.It should be understood that various alternatives to the embodiments ofthe invention described herein may be employed in practicing theinvention. It is intended that the following claims define the scope ofthe invention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

The invention claimed is:
 1. A medical device comprising: a substrate;and a coating on at least a portion of said substrate, wherein thecoating comprises a plurality of layers, wherein at least one layercomprises a pharmaceutical agent that is crystalline, wherein the deviceis adapted to free at least a portion of the coating from the substrateupon stimulation of the coating, wherein the coating comprises at leastone of a non-absorbable polymer and a bioabsorbable polymer, and whereinthe portion of the coating freed from the device comprises the at leastone of the non-absorbable polymer and the bioabsorbable polymer, andwherein at least about 35% of the coating is adapted to be freed fromthe substrate upon stimulation that lasts at most 20 seconds.
 2. Thedevice of claim 1, wherein the crystalline pharmaceutical agent is not amicrocapsule.
 3. The device of claim 1, wherein the substrate comprisesa balloon.
 4. The device of claim 1, wherein the pharmaceutical agentand a polymer are in the same layer, in separate layers, or formoverlapping layers.
 5. The device of claim 1, wherein the plurality oflayers comprise five layers deposited as follows: a first polymer layer,a first pharmaceutical agent layer, a second polymer layer, a secondpharmaceutical agent layer and a third polymer layer.
 6. The device ofclaim 1, wherein the pharmaceutical agent comprises a macrolideimmunosuppressive drug.
 7. The device of claim 6, wherein the macrolideimmunosuppressive drug comprises one or more of rapamycin,40-0-(2-Hydroxyethyl)rapamycin (everolimus), 40-0-Benzyl-rapamycin,40-0-(4′-Hydroxymethyl)benzyl-rapamycin,40-0-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-0-Allyl-rapamycin,40-0-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin,(2′:E,4′S)-40-0-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin40-0-(2-Hydroxy)ethoxycar-bonylmethyl-rapamycin,40-0-(3-Hydroxy)propyl-rapamycin, 40-0-(6-Hydroxy)hexyl-rapamycin,40-0-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin,40-0-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin,40-0-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin,40-0-(2-Acetoxy)ethyl-rapamycin, 40-0-(2-Nicotinoyloxy)ethyl-rapamycin,40-0-[2-(N-Morpholino)acetoxy]ethyl-rapamycin,40-0-(2-N-Imidazolylacetoxy)ethyl-rapamycin,40-0-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin,39-0-Desmethyl-39,40-0,0-ethylene-rapamycin,(26R)-26-Dihydro-40-0-(2-hydroxy)ethyl-rapamycin, 28-0-Methyl-rapamycin,40-0-(2-Aminoethyl)-rapamycin, 40-0-(2-Acetaminoethyl)-rapamycin,40-0-(2-Nicotinamidoethyl)-rapamycin,40-0-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin,40-0-(2-Ethoxycarbonylaminoethyl)-rapamycin,40-0-(2-Tolylsulfonamidoethyl)-rapamycin,40-0-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin,42-Epi-(tetrazolyl)rapamycin (tacrolimus), and42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin(temsirolimus).
 8. The device of claim 1, wherein the pharmaceuticalagent is rapamycin.
 9. The device of claim 1, wherein the pharmaceuticalagent is at least 50% crystalline.
 10. The device of claim 1, whereinthe pharmaceutical agent is at least 75% crystalline.
 11. The device ofclaim 1, wherein the pharmaceutical agent is at least 90% crystalline.12. The device of claim 1, wherein the coating is formed on saidsubstrate by a process comprising at least one of: depositing a polymerby an e-RESS, an e-SEDS, or an e-DPC process, and depositing thepharmaceutical agent by an e-RESS, an e-SEDS, or an e-DPC process. 13.The device of claim 12, wherein the process of forming the coatingprovides improves adherence of the coating to the substrate prior todeployment of the device and facilitates dissociation of said coatingfrom said substrate upon stimulation.
 14. The device of claim 1, whereinthe device is adapted to transfer less than about 10% of the coatingabsent stimulation of the coating.
 15. The device of claim 1, whereinthe coating comprises a bioabsorbable polymer.
 16. The device of claim15, wherein the bioabsorbable polymer comprises at least one of:Polylactides (PLA); PLGA (poly(lactide-co-glycolide); Polyanhydrides;Polyorthoesters; Poly(N-(2-hydroxypropyl) methacrylamide);DLPLA-poly(dl-lactide); LPLA-poly(l-lactide); PGA-polyglycolide;PDQ-poly(dioxanone); PGA-TMC-poly(glycolide-co-trimethylene carbonate);PGA-LPLA-poly(l-lactide-co-glycolide);PGA-DLPLA-poly(dl-lactide-co-glycolide);LPLA-DLPLA-poly(l-lactide-co-dl-lactide); andPDO-PGA-TMC-poly(glycolide-co-trimethylene carbonate-co-dioxanone), andcombinations, copolymers, and derivatives thereof.
 17. The device ofclaim 15, wherein the bioabsorbable polymer comprises between 1% and 95%glycolic acid content PLGA-based polymer.
 18. The device of claim 1,wherein at least about 50% of the coating is adapted to be freed fromthe substrate upon stimulation.
 19. The device of claim 1, wherein thedevice is adapted to free all of the coating upon a single stimulationof the coating.